Florence T. Bourgeois MD, MPH, is assistant professor of Pediatrics and Emergency Medicine at Harvard Medical School, faculty in the Computational Health Informatics Program, and Scientific Director of the Biobank for Health Discovery at Boston Children’s Hospital
Every day, more than half of children seen in outpatient clinics are prescribed a medication that is not FDA approved for the child’s age or diagnosis. Such off-label prescribing is widespread across pediatric conditions and treatment settings and as many as 90 percent of pediatricians have knowingly prescribed off-label medications.
Off-label prescribing has evolved by necessity. Most new medications are developed and tested in adults and lack marketing authorization in children. In fact, even though they represent a quarter of the U.S. population, children are routinely excluded from clinical trials. In 2015, of more than 19,000 interventional trials registered on ClinicalTrials.gov, only 6 percent focused on children.
These treatment practices may result in serious harms. One notable example involved the off-label use of verapamil to treat a type of tachycardia in children, a practice later implicated in life-threatening hypotension in children. Similarly, the antimicrobial chloramphenicol was used without adequate testing in children and became associated with “gray baby syndrome”, a condition in which children suffered fatal circulatory collapse.
A number of laws have been implemented in the past 15 years to create both incentives and requirements for pharmaceutical companies to conduct pediatric drug research. These include the Best Pharmaceuticals for Children Act (BPCA), passed in 2002, and the Pediatric Research Equity Act (PREA), enacted a year later. Under PREA, sponsors must provide information on the safety and efficacy of a new drug in children at the time they submit their application to the FDA for approval in adults. This policy has led to a number of additions to drug labels to encourage safe use of medications in children.
However, as we point out in a recent JAMA article, these laws have substantial limitations. For one, they don’t cover orphan therapies — medications used to treat rare diseases. This exemption is concerning for children, because the majority of rare diseases start in childhood and more than half of orphan drugs affect conditions that occur in children.
Consider, for example, pulmonary arterial hypertension, a rare disease with a high mortality rate that occurs in both children and adults. A number of drug therapies are available for adults, but none have FDA approval for children. As a result, physicians treating children with this condition have no choice but to use medications off-label, on a trial-and-error basis, with limited data on their safety in these young patients.
In addition to closing this loophole, we need to improve compliance by drug companies and other sponsors with pediatric trial obligations. Currently, many sponsors request deferrals, leading to delays in conducting the mandatory pediatric research for as many as 55 percent of products. One example is methoxy polyethylene glycol-epoetin, a drug approved by the FDA in 2007 for adults with chronic renal failure. Although the company was required to test the drug in children and complete a dose-finding study within two years, it instead requested multiple deferrals. To date, the pediatric trials have not been completed and the drug is available to children only in an off-label manner, without pediatric dosing guidelines.
And once a drug trial is done in children, we need to improve access to the results so that clinicians can use the information. Many pediatric trials are never published in medical journals and many that are published do not accurately reflect the results of the trials, particularly the safety of the products when used in children. The current policies should be amended to require that these valuable pediatric trial data are accessible in a timely and comprehensive fashion.
The passage of policies to improve pediatric drug research marked an important chapter in efforts to increase the clinical study of medications in children. Modernizing these programs would help ensure continued progress toward safe and effective drug therapy in children.
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