By AMERICAN HEART ASSOCIATION NEWS

The Food and Drug Administration and three major health organizations are calling for a shakeup in how drugs are developed and tested in children with heart disease and other conditions.

In a health policy statement issued Thursday, the groups said drug trials must be flexible enough to overcome enrollment problems and other barriers to research in children with heart disease, while giving pediatricians proof that the treatments they’re using actually work.

The statement is “really apropos to the problem that exists in pediatrics,” said Thomas Kimball, M.D., medical director of the heart institute at Cincinnati Children’s Hospital Medical Center in Ohio, who was not involved in writing the new statement.

“As a clinical cardiologist, there’s no pediatric evidence of why I should use the drugs I use,” he said.

Researchers studying medications in children face many obstacles, according to the statement. Children change rapidly as they grow and develop, which requires adjustments in drug doses. It’s difficult to determine long-term drug effects that may impact children decades later. And finding enough kids to study in a clinical trial is tough considering the rarity of cardiovascular diseases at such a young age and the ethical considerations that prevent children from undergoing invasive tests.

Communication is another barrier, Kimball said.

“You and me, if we’re given a drug we can say we feel better, describe the benefits,” but a baby can’t talk to you or do an exercise stress test, he said.

The single biggest barrier, however, is the lack of funding, Kimball said. Drug manufacturers focus on adult drugs because “that’s where the money is.”

The FDA made it a priority to address issues plaguing pediatric heart research after the American College of Cardiology, the American Heart Association and the American Academy of Pediatrics met with the agency in 2014 to discuss sildenafil, marketed as Revatio, for children, according to Craig Sable, M.D., lead author of the statement.

“The meeting with FDA was the first of its kind,” said Sable, associate division chief of cardiology at Children’s National Health System in Washington, D.C. Recently, he said, there has been a greater sense of collaboration with the agency, including the FDA’s suggestion to issue the new statement alongside the three health groups.

Sildenafil, best known by the brand name Viagra, is used to treat pulmonary hypertension, a sometimes fatal heart and lung disease that may affect as many as one to two of every 1,000 newborns in the United States. The drug is used off-label to treat the condition in children.

From 2003-2011, two clinical trials studied sildenafil in 234 children ages 1 to 17. The first compared low, medium and high doses of sildenafil to a placebo for four months; then patients could do a study extension for at least three years.

When the trial concluded, researchers found a trend for more deaths in some children taking high doses of the drug, which led to a strong warning from the FDA in 2012: The drug should not be prescribed to children with pulmonary hypertension.

“The FDA felt it had no choice but to issue a warning” due to the increased deaths, said Sable, adding that the warning led some insurers to drop coverage of sildenafil for children.

“I understood why the FDA didn’t approve the drug for use in children, but I didn’t understand the strength of the warning,” said Dunbar Ivy, M.D., lead author of the sildenafil trial and professor of medicine in pediatric cardiology at the University of Colorado School of Medicine in Aurora.

Ivy said he and colleagues had used sildenafil off-label for nearly a decade without any unexplained deaths.

Sable said parents were disappointed by the FDA warning because sildenafil was one of few treatments for children with pulmonary hypertension. “It’s still a very hard disease to control,” he said.

In 2014, the FDA relaxed its initial warning, suggesting that doctors could prescribe the drug to children if they felt the benefits outweighed the risks.

This judgment call is the case for most drugs prescribed by pediatric heart specialists, Sable said.

Less than half the drugs approved in the United States have data supporting their use in children, and nearly all hospitalized children get at least one off-label medication, according to the statement.

Future studies in children should be adapted so that researchers can analyze data sooner, adjust drug doses or conduct early tests to determine a drug’s benefit, the statement said. Combining computer models of disease with genetic information could one day be used to decrease the number of children required in research studies, the authors wrote.

Ivy is encouraged by the FDA’s efforts to work with pediatric researchers, “but there’s no solution yet.”

Sable said when it comes to preventing and treating cardiovascular disease in childhood, “we have so many years of life to save and improve upon. The stakes are high.”