Evidence on Pediatric Drugs Is Deficient Despite Legislation

Daniel M. Keller, PhD

May 03, 2012

May 3, 2012 (Boston, Massachusetts) — The amount of clinical trial research on drugs for children is not keeping up with the burden of disease in children, with developing countries showing the most severe deficiency of evidence.

This finding was reported by Florence Bourgeois, MD, MPH, assistant professor at Harvard Medical School and member of the division of emergency medicine at Boston Children's Hospital in Massachusetts, here at the Pediatric Academic Societies 2012 Annual Meeting.

Problems lie in the low number of randomized trials and the insufficient evaluation of drug safety for children. Dr. Bourgeois said that three quarters of drugs are not approved for use in children, but clinicians extrapolate evidence derived from studies of adults and prescribe the drugs to children, essentially on a trial-and-error basis, unaided by any age-specific research on dosing, safety, or efficacy.

Using the ClinicalTrials.gov database (containing 89% of all registered clinical trials globally that started between 2006 and 2011), Dr. Bourgeois and colleagues were able to compare pediatric trial characteristics and quality indicators with adult trials. They selected trials for conditions that impose a heavy burden of pediatric disease, based on the World Health Organization Global Burden of Disease report.

These conditions differ, depending on the development status of countries. For high-income countries, the greatest disease burden results from asthma, migraine, schizophrenia, bipolar disorder, and depression. For middle- and low-income countries, malaria, diarrheal disease, respiratory infections, depression, and HIV/AIDS are the main sources of disease burden in children.

Of the 2440 studies identified, encompassing 608,438 subjects, 77% of those on high-burden conditions in middle/low-income countries involved at least 1 site in those countries, "which indicates that these trial results will also be pertinent to subjects in those countries," Dr. Bourgeois said.

"Overall, of the 9 conditions that we studied, 59.9% of the total disease burden is borne by pediatric patients or by children," she reported. "In comparison, only 12% of all the trials are pediatric trials, and these 2 proportions are significantly different [P < .001]."

In high-income countries, 21.4% of disease burden is borne by children; in middle/low-income countries, that figure is 61.9%. However, the proportion of trials that are pediatric are about the same (9.8% in high-income countries vs 11.9% in middle/low-income countries) — showing that the proportion of trials in middle/low-income areas are even more lacking in addressing pediatric diseases of concern than they are in high-income countries.

More adult trials than pediatric trials received any industry support (51.5% vs 36.6%). Fewer pediatric than adult trials involved safety (7.9% vs 17.0%; P < .001) or pharmacokinetic/pharmacodynamic (16.1% vs 22.2%; P = .02) end points. The pediatric ones were somewhat more likely to be registered before the start of the trial and had a higher probability of being published (P = .04 for both).

Dr. Bourgeois and colleagues found no significant differences between pediatric and adult trials in terms of randomization, active comparator groups, double blinding, or study length. So although pediatric trials are deficient in relation to the amount of disease burden in children, with the greatest deficiency in developing countries, there is no consistent evidence to suggest that the trials that are carried out are of lower quality than adults trials.

She noted that some limitations of this study are that ClinicalTrials.gov might not include all drug trials and that full study protocols were not available.

She said the implications of these findings are that there is a need to strengthen the research agenda for common pediatric conditions and that support for such research needs to be encouraged from both nonprofit and commercial funding sources.

"To me, the most surprising finding was not just that there is truly less pediatric research happening, compared with adult research, but the fact that this is for common conditions," Dr. Bourgeois told Medscape Medical News. "It's not just for rare disease; it's for common conditions such as asthma that we're really cutting children short."

Session moderator Leonardo Trasande, MD, MPP, associate professor of pediatrics, environmental medicine, and health policy at New York University in New York City, said that "it is unfortunate to continue to see a relative dearth of pediatric research after federal legislation that was intended to encourage studies of drug effects and safety in children."

The Best Pharmaceuticals for Children Act was passed in 2002 and again in 2007, but is set to expire late in 2012 unless made permanent by Congress. The Pediatric Research Equity Act was passed in 2003 and reauthorized in 2007.

Dr. Trasande told Medscape Medical News that financial incentives do not appear to be sufficient to encourage manufacturers to carry out enough trials on drugs for children.

"Clearly, market share for pediatric drugs is much more modest than for adults, and that may suggest a role for entities outside the private sector," he said. "Many of those drugs are actually already generic in form; therefore, there might not be the same market for those studies.... I think this is an area that policy makers need to weigh in on and decide about the need for filling niches of research." Furthermore, he said, more attention needs to be paid to prevention.

Dr. Bourgeois noted additional barriers to the needed research, which include "ethical challenges, low prevalence of disease in children, and simply the low profitability potentially of drugs that have been developed in children."

She pointed out that in Europe, mandates on drug manufacturers have been successful in increasing pediatric testing of drugs that are introduced into the market. "In the United States, there is evidence that a number of these Acts, or at least the Best Pharmaceuticals for Children Act, has resulted in labeling changes for many drugs. This means that there's improved information on how these drugs should be used in children," she said.

But often, information about the use of drugs in children has come from expert opinion and trial and error. "I think having evidence-based guidelines on the optimal use of these drugs would be terrific, and you really can only obtain that through randomized clinical trials," Dr. Bourgeois explained. Reports of such trials would help to disseminate the information more widely than just word of mouth on expert opinions.

Dr. Bourgeois and Dr. Trasande have disclosed no relevant financial relationships.

Pediatric Academic Societies (PAS) 2012 Annual Meeting. Abstract 1135.8. Presented April 28, 2012.


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