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Study: ADHD Drug Approvals Rarely Include Long-Term Efficacy and Safety

Authors find gaps in FDA approval process

During the last 60 years, the FDA approved 20 medications for attention deficit/hyperactivity disorder (ADHD) based on clinical trials that were not designed to study their long-term efficacy and safety or to detect rare adverse events, according to researchers at Boston Children’s Hospital.

The new study — published in PLoS One — highlights gaps in how the long-term safety of drugs intended for chronic use in children is assessed as part of the FDA’s approval process.

“This study doesn’t address whether ADHD drugs are safe, though their safety has since been established through years of clinical experience,” said senior author Kenneth Mandl, MD, MPH. “Instead, 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.”

According to the Centers for Disease Control and Prevention (CDC), 11% of children in the U.S. between 4 and 17 years of age — or about 6.4 million children — have been diagnosed with ADHD. On average, children prescribed ADHD medications take them for several years.

To understand how extensively the long-term safety of common ADHD medications had been studied before going on the market, the researchers reviewed the clinical trial data included in the FDA-approval labeling for 20 drugs, going as far back as the original FDA approval of methylphenidate (Ritalin) in 1955.

The team identified 32 clinical trials involving the 20 drugs. Only five of these studies were focused specifically on drug safety. The team calculated that each drug was tested in a median of 75 patients before FDA approval, with a median trial duration of 4 weeks. Eleven of the 20 drugs were approved after having been tested in fewer than 100 patients, and 14 in fewer than 300 patients. Seven drugs that the FDA had previously approved for other conditions, such as obesity, were approved for the treatment of ADHD without any condition-specific trials or trials in children.

For context, the authors note that the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) — a forum for best practices in drug development — recommends that drugs intended for chronic use in non–life-threatening conditions, such as ADHD, should be tested in a minimum of 300 to 600 patients for at least 6 months, in a minimum of 100 patients for at least 1 year, and in approximately 1,500 patients total before regulatory approval.

“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 said. “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.”

Of note, six of the drugs received FDA approval with the caveat that the manufacturers conduct post-marketing surveillance studies of long-term safety. However, based on the records the researchers reviewed, only two of those requested studies were ever conducted.

“One approach used by the FDA to increase our knowledge of rare adverse drug events and the long-term safety of drugs is to require pharmaceutical companies to conduct post-marketing trials after a drug is approved,” said first author Florence Bourgeois, MD, MPH. “However, historically there has been little enforcement of this requirement, and sponsors have not been conducting the requested post-marketing trials.”

Mandl and Bourgeois see the results of their study as a call for increased regulatory emphasis on drugs’ long-term safety and efficacy, particularly ones prescribed on a chronic basis.

Source: Boston Children’s Hospital; July 9, 2014.

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