Seizure drug trials sought at Children's
Children's Hospital Boston wants to participate in a clinical trial comparing two drugs commonly given to children suffering life-threatening seizures, but because treatment must start within five minutes of the child's arrival in the emergency room, parental consent will not be obtained until after one of the medications is given.
The hospital is seeking approval for this unusual arrangement from an internal review board, and also plans to inform the public about the study, which would be one of the first times an emergency waiver of consent will be sought for children, said Dr. Michael Shannon. He is chief of emergency medicine at Children's and the principal investigator for the site, one of 11 across the country seeking to participate in the study sponsored by the National Institute of Child Health and Human Development.
"This study stems from the recognition that we regularly give medications to children that have not been adequately tested for their safety and their effectiveness, which is a huge problem that must be solved," Shannon said in an interview.
It is "appalling," he said, that between 70 percent and 80 percent of drugs to treat children are used off-label, meaning doctors use their broad discretion to prescribe drugs even though they have not been approved for use in children. "This is a first step of a very important, albeit-long path to turn that around."
Parents usually must give their permission before a child is enrolled in a study and after being informed about the risks and benefits of a treatment, but leaders of the nationwide study say there isn't time for such discussions before treating seizure patients. In this instance, parents will be told about the study after the child's condition is stable. If they choose to participate, blood samples will be taken from the child, and the child and parent will be interviewed by phone 48 hours and 30 days later.
"We have consulted with a wide range of ethicists, experts, and government officials about this study to ensure that we protect patients' safety," Dr. Jill Baren of the Children's Hospital of Philadelphia, co-principal investigator of the study, said in a statement from the child health institute.
Shannon said Children's submitted a proposal to the hospital's internal review board in March. He will be speaking to focus groups and visiting community health centers and seizure disorder clinics to inform people about the proposed study and get their reaction, he said.
The kind of seizures being studied, called status epilepticus, happen to children with or without epilepsy. They can occur while the child has a high fever, low blood sugar, or an infection of the central nervous system, according to the institute. These seizures can cause brain damage or, in 4 percent of cases, death. Status epilepticus affects four to eight children out of 1,000 before they reach age 15.
Shannon said about 200 to 250 children come to the Children's emergency department each year with this form of seizure. Some are the first seizure the child has ever had, and others occur in children who are known to have a seizure disorder, but despite being on medications and under a neurologist's care, they have "breakthrough" seizures.
The two drugs commonly used to treat these children are diazepam, better known as Valium, and lorazepam, or Ativan. Diazepam is approved by the US Food and Drug Administration for use in children with this kind of seizure, but lorazepam is not, although it is widely used by physicians off-label.
The accumulation of more than 15 years of clinical experience has made lorazepam, which is approved for adults, the standard of care in children, Shannon said. Its effects may have longer duration than diazepam, he said, but otherwise the two drugs appear to be equivalent. That's an important ethical consideration in a clinical trial that randomly assigns one drug or another to a child, he said. Both drugs are currently used at Children's.
Normally, physicians decide which of these drugs to use, but in the study, a computer will randomly assign children to get either diazepam or lorazepam in order to reduce bias influencing the trial's results.
Dr. Michael Grodin, director of medical ethics at Boston University School of Public Health, said in an interview that the proposed trial appears to meet ethical standards for conducting research with participants who are vulnerable because they are children and because in an emergency situation they can't give consent.
"If you don't do research either in an emergency situation or with children, you'll never know if these things are safe and effective," said Grodin, who is not involved in the study. "You can be giving treatments to people that not only are not helpful but even harmful unless you do the study to determine if they are safe and effective."
