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Long-term safety, efficacy not measured by trials for ADHD drugs

Rare adverse events or long-term safety and efficacy have not been measured through clinical trials of attention-deficit/hyperactivity disorder drugs, according to recent study findings published in PLOS ONE.

“This study doesn’t address whether ADHD drugs are safe, though their safety has since been established through years of clinical experience,” Kenneth Mandl, MD, MPH, of Boston Children’s Hospital, said in a press release. “Instead, we point to the need for an agenda emphasizing improved assessment of rare adverse events and long-term safety through postmarketing trials, comparative effectiveness trials and more active FDA enforcement.”

Kenneth Mandl

Mandl and colleagues identified all ADHD medications approved by the FDA and evaluated the clinical trials that measure safety and efficacy to determine number participants and length of exposure to the drugs.

“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.”

Overall, 20 drugs were approved by the FDA during 32 clinical trials. However, drug safety was only tested in five. Efficacy trials with an active comparator were used for six of the drugs, whereas all other drugs were compared with a placebo.

Most commonly, there was a median of 75 patients in the clinical trials before FDA approval, with a median trial length of 4 weeks. Overall, 11 drugs were approved with fewer than 100 patients and 14 in fewer than 300 patients.

“One approach used by the FDA to increase our knowledge around rare adverse drug events and the long-term safety of drugs is to require pharmaceutical companies to conduct postmarketing trials after a drug is approved,” study researcher Florence Bourgeois, MD, MPH, of Boston Children’s Hospital, said in a press release. “However, historically there has been little enforcement of this requirement and sponsors have not been conducting the requested postmarketing trials.”

FDA approval was provided for six drugs if the manufacturers conducted postmarketing surveillance; however, only two of the studies were conducted.

“In conclusion, clinical trials conducted for the approval of many ADHD drugs have not been designed to assess rare adverse events of long-term safety and efficacy,” the researchers wrote. “Despite the large number of available drugs, comparative effectiveness trials are rare. While postmarketing studies can fill in some of the gaps, FDA enforcement is important to ensure that postmarket surveillance studies are completed. An ambitious agenda to assess long-term outcomes in the millions of patients on these medications is warranted.”

Disclosure: Two researchers report financial ties with the National Institute of Child Health and Human Development and the NIH.