Only a third of Federally mandated ‘post-marketing’ pediatric drug trials are complete

too few mandated pediatric drug trials are getting done
Despite new requirements, pediatric drug trials largely aren’t getting done. (ADOBE STOCK)

The FDA requires clinical studies of new drugs in pediatric populations, since many drugs developed for use in adults are also used in children. These studies are often “post-marketing” trials after the drug is approved in adults. But an audit by researchers at Boston Children’s Hospital found that only about a third of these mandatory trials were completed within an average of seven years. As a result, most new drug labels continue to lack child-specific information, and most FDA-approved drugs remain untested in children.

Findings were published online today by JAMA Pediatrics.

“More than 50 percent of all drugs approved by the FDA lack information on how to safely and effectively use the drug in children,” says Florence Bourgeois, MD, MPH, of the Pediatric Therapeutics and Regulatory Science Initiative at Boston Children’s Hospital ( “As a clinician, I was struck early on by how little evidence we often have to guide medication use in children. Although the FDA has an established process to ensure medicines are safe and effective in adults, this has historically been lacking for children.”

Mandated studies in children

In 2003, Congress passed the Pediatric Research Equity Act (PREA). It authorizes the FDA to mandate clinical trials in pediatric populations to assess drug safety and effectiveness, and to inform appropriate dosing and administration in different age groups.

We are still seeing long delays between the approval of a drug and the availability of pediatric information. 

When it was passed, PREA allowed manufacturers to seek deferrals from pediatric studies in certain cases and complete the studies after the drug was approved. Over time, implementation has relied heavily on deferrals. In 2007, when PREA was renewed, it was decided to make all deferred studies “post-marketing” trial requirements.

The JAMA Pediatrics study assessed the implementation of these studies, both for new drugs and for new indications for approved drugs. From 2007 to 2014, the FDA approved 114 new drugs and new indications subject to PREA pediatric study requirements.

These approvals required a total of 222 pediatric post-marketing studies, yet as of December, 2017, only 34 percent of these studies were completed. Of these, 45 percent had results reported in a journal.

At the time of approval, only 16 percent of drugs approved with post-marketing studies had any information in their labels on  efficacy, safety or dosing in children.  After a median follow-up of seven years, this increased to only 41 percent.

Perpetuating off-label prescribing

“We have a powerful legislation in place that sets the standard that all drugs relevant to pediatric health hit the market with some information on their safety and efficacy in children,” says Bourgeois, who is also a member of the Computational Health Informatics Program at Boston Children’s Hospital. “Unfortunately, we are still seeing long delays between the approval of a drug and the availability of pediatric information. This perpetuates off-label drug use that may be unsafe or ineffective.”

Bourgeois says that PREA requirements apply only to drugs that are deemed relevant to pediatric conditions. Drugs with orphan indications are exempt from any pediatric study requirements. “But we feel that pediatric studies should also be performed for orphan drugs on a case-by-case basis, since many orphan diseases start in childhood,” says Bourgeois.

She notes that PREA was broadened in 2017 to apply to all oncology products, even those with an orphan drug designation. This type of amendment to PREA might benefit other pediatric conditions as well, she says.

Strengthening PREA?

Bourgeois and her colleagues suggest additional FDA oversight and use of enforcement tools to ensure that pediatric studies are completed. They also recommend reevaluation of the deferral process to identify trials that could be required to be finished sooner, and further examination of the barriers to trial completion.

“Our goal is to strengthen the PREA legislation,” says Bourgeois. “This will require not only a careful examination of how the legislation has been implemented, but also consideration of the challenges that industry is likely encountering when trying to complete these trials. We may need additional conversations to better understand how to maximize our resources and obtain pediatric data for the drugs that are most likely to impact children’s health.”

This work was supported by a grant from the Burroughs Wellcome Fund.

Source: TJ Hwang, et al. Completion and Reporting of Mandatory Pediatric Post-Marketing Trials under the Pediatric Research Equity Act. JAMA Pediatrics 2018 Nov 19.