A hole in the FDA’s approval process for pediatric drugs

ADHD long term drug safety rare adverse events FDA approval Kenneth Mandl Florence BourgeoisYou’d think drugs meant to be taken by children for years would be studied in children for a long time to measure their long-term safety.

You’d think drugs for a condition affecting millions of children would be tested in many, many children to catch any rare side effects.

You’d think all this would happen before the Food and Drug Administration, an agency known for its strict criteria, approved them for marketing.

But if a new PLoS ONE paper by Boston Children’s Hospital’s Florence Bourgeois, MD, MPH, and Kenneth Mandl, MD, MPH, is any indication, you’d be wrong.

In it, the pair reports that the FDA approved 20 attention deficit hyperactivity disorder (ADHD) drugs over the last 60 years without what would be considered sufficient long-term safety and rare adverse event data.

Their findings, they say, point to larger issues in how the FDA’s approval process addresses the long-term safety of drugs intended for chronic use in children.

Small numbers for big numbers

According to statistics kept by the Centers for Disease Control and Prevention, roughly one in nine children in the United States—about 6.4 million children—has been diagnosed with ADHD.

Mandl—who is Boston Children’s chair in biomedical informatics and population health and director of the Intelligent Health Laboratory in Boston Children’s Informatics Program—says he became interested in the question of ADHD drug approval when advising an insurance carrier about the prescriptions it covers. “I was struck that many of the ADHD drugs on the market had been studied for only a few weeks before FDA approval.”

He and Bourgeois decided to delve deeper, reviewing the FDA approval packages and pivotal clinical trial data for 20 drugs as far back as Ritalin®’s approval in 1955.

All told, they found 32 clinical trials for the 20 drugs. When they calculated the trials’ median duration, they came up with a surprisingly short number—four weeks.

They then tallied up the sizes of the trials, finding that 11 of the 20 drugs were approved after having been tested in fewer than 100 patients, and 14 in fewer than 300. Seven drugs that the FDA had previously approved for other conditions, such as obesity, were approved for ADHD without any trials in ADHD or in children at all.

Ritalin ADHD long term drug safety rare adverse events FDA approval Kenneth Mandl Florence Bourgeois
Ritalin-SR ®, one of the ADHD drugs reviewed in Mandl and Bourgeois' study (Image credit: Sponge/Wikimedia Commons)

How could this happen? The findings fly in the face of guidelines developed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)—a forum for best practices in drug development. ICH recommends that before approval drugs intended for long-term use for non-life-threatening conditions (like ADHD) should be tested in:

  • a minimum of 300 to 600 patients for at least six months, and
  • a minimum of 100 patients for at least one year, and
  • about 1,500 patients in total

Both the National Institutes of Health and the European Medicines Agency (the FDA’s European equivalent) have, in the past, pointed out the importance of proper long-term study of ADHD drugs. And in at least one case—the approval of Focalin XR®—the FDA’s own reviewers voiced concerns over the brevity of trials.

Mandl believes that the approval trials’ designs emphasized short-term efficacy over long-term effects.

“ADHD drugs are so effective at producing a behavioral effect quickly that one can measure a statistically significant treatment effect rapidly and with relatively few patients,” Mandl says. “However, in the real world, these drugs are prescribed often for years, not for a few weeks, and long-term cognitive effects were never measured during the approval process.”

Ex post facto

Mind you, the FDA does have a process for addressing long-term safety and rare event issues—the post-marketing surveillance study (one of a collection of assessment activities that some refer to as Phase IV of drug development). Ideally, such studies would collect data on a drug’s real-world use for a long time after its market entry.

“However, historically there has been little enforcement of this requirement,” notes Bourgeois, an emergency medicine physician. (Bourgeois also studies topics in pediatric drug development, such as alignments, or the lack thereof, between drug research and development priorities and the global burden of diseases.)

Lack of enforcement seems to be the case here. Bourgeois and Mandl found that the FDA requested post-marketing trials for just six of the 20 drugs they reviewed, and only two of those studies were ever conducted.

Mandl cautions that their analysis wasn’t intended to raise alarm about the safety of available ADHD drugs. “Their safety has since been established through years of clinical study,” he says.

Rather, their goal, he says, was to call for greater regulatory emphasis on drugs’ long-term safety and efficacy, especially for drugs that children take for years at a time.

“We point to the need for an agenda emphasizing improved assessment of rare adverse events and long-term safety through post-marketing trials, comparative effectiveness trials and more active FDA enforcement.”