Jan. 5, 2004 Enrolling children with asthma in the placebo arm of a clinical trial is common, harmful and ethically unjustified argue researchers from the University of Chicago and the National Institutes of Health (NIH) in the January 2004 issue of Pediatrics. After a systematic review of all clinical asthma trials involving children in the United States published between 1998 and 2001, the researchers found that children with asthma were more than twice as likely to be harmed -- defined as forced to withdraw from the trial due to asthma exacerbation -- if they did not receive standard asthma therapy compared to children who received standard treatment.
Although established guidelines recommend anti-inflammatory medications for all children and adults with mild-persistent, moderate or severe asthma, 45 of the 70 published studies compared a drug against a placebo. All 45 studies involved subjects under the age of 18 and 14 of the studies involved only children.
"This is problematic," said study co-author Lainie Friedman Ross, M.D., Ph.D., associate professor of pediatrics and assistant director of the MacLean Center for Clinical Medical Ethics at the University of Chicago. "These children have been exposed to unnecessary risks and harm because the very medication they depend on is being withheld from them during these studies."
The research also revealed serious concerns with current asthma practice. In only 18 of the 70 studies, those subjects with more than mild asthma were actually taking anti-inflammatory medications prior to joining the study. Although 22 of the studies required all subjects to begin or continue to take appropriate medications, 48 of the studies did not. In six trials, subjects who had been on appropriate anti-inflammatory therapy prior to the study were taken off these medications.
"Children aren't on medications before the study for a variety of reasons," Ross said. "It may be a lack of access to mediations and pediatric care, a lack of family education and understanding regarding the need for daily medication, and/or a failure of health care providers to prescribe appropriate treatment." Ross noted whatever the reason, it's "unconscionable" that children are not properly treated when joining these studies. "Those who don't get the experimental drug should get standard treatment."
The researchers chose to scrutinize asthma research because the respiratory disease is one of the most common chronic conditions of childhood -- nearly 4.5 million children in the United States have it. In 1998, asthma resulted in more than 200 deaths; 174,000 hospitalizations; more than 867,000 emergency room exams; 5.8 million visits to the doctor's office; and 10 million missed school days. Many patients deal with severe discomfort that may be associated with anxiety.
The researchers examined the impact policy initiatives in the 1990s have had on the inclusion of children in clinical trials. In recent years, the NIH and the Food and Drug Administration have been attempting to involve more children earlier in the drug development process to ensure that new treatments are effective and appropriately dosed for children of all ages. But the researchers noted that only one of 52 studies involving children and adults analyzed the effects of the experimental medication on the pediatric subjects.
"The goal of the policies is to place some children at risk for the benefit of children as a class, but unless researchers do subset analyses, we are not getting any benefit to children as a class," Ross noted.
Many of the asthma studies examined were not considered groundbreaking. The clinical trials were testing therapies that were similar to what already was available, and nearly all of them were funded by pharmaceutical companies.
"These 'me too' studies should not be designed as placebo-controlled trials" Ross said. "No study subject should be denied standard medications when the standard medication is so well studied and is known to prevent serious morbidity and mortality."
In one of the studies examined, Ross and her colleagues found that the researchers even admitted in their discussion: "Asthma symptoms would be expected to worsen in the placebo group during the treatment period because these patients were dependent on inhaled steroids, but were not allowed treatment with inhaled steroids while in the study."
Almost all the clinical trials received Institutional Review Board approval, so they were scrutinized for their research ethics. Ross explained that IRBs have two functions: to ensure that subjects are informed to give consent and to protect subjects. She argues that "IRBs do a better job ensuring consent than in protecting subjects, in part because of our cultural attitude that individuals can decide what is in their best interest." But Ross said IRBs should place greater focus on protection, particularly for vulnerable populations like children.
Ross described the criteria used in many clinical asthma trials involving children as "flawed." She said researchers and institutional review boards need to re-evaluate how these types of clinical asthma trials are conducted in the 21st century.
Ross' work on children in research was funded by a NIH grant. Additional authors of the paper are Benjamin Wilfond, M.D., a bioethicist at the National Human Genome Research Institute, and M. Justin Coffey, a University of Chicago medical student.
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