US regulators have released new recommendations for manufacturers of psychoactive drugs—including sleep aids—following several warnings by the US Food and Drug Administration (FDA) that some drugs were causing patients to get into car accidents hours after the effects of the drug should have worn off.
Sleep drugs have long been on FDA's radar, primarily due to their association with impaired driving. The concern has been that some patients respond atypically, resulting in elevated levels of the drug which last until the next morning and impact activities that "require alertness, including driving."
In January 2013, FDA announced that it would require manufacturers of sleep drugs containing zolpidem to submit labeling changes to the agency. The requirement was seen as highly unusual in that the changes disproportionately affected women, whose recommended dose was cut in half.
“Over the years, FDA has received spontaneous adverse event reports of driving impairment and motor vehicle accidents associated with zolpidem, but these reports lacked the information necessary to fully understand whether and how zolpidem affected people’s mental alertness and ability to drive,” Ellis Unger, director of the Office of Drug Evaluation, said at the time. “Recently, data from clinical trials and other types of studies have become available, which allowed FDA to better characterize the risk of next-morning impairment.”
Read more about FDA's required labeling changes for zolpidem-containing medicines here.
Read FDA's explanation of why they restricted the medication here.
Then, in May 2014, FDA warned the public about a second sleep-aid drug, Lunesta (eszopiclone), saying it, too, was associated with impaired driving.
"Data show that eszopiclone levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving, even if they feel fully awake," FDA said in a statement.
Similar to zolpidem-containing drugs, FDA said it would be reducing by half the recommended dose for both men and women, and recommend that patients take the lowest-recommended dose capable of treating their insomnia.
Read more about FDA's required labeling changes for eszopiclone-containing medicines here.
Now FDA is out with a new draft guidance document meant to explain to the pharmaceutical industry how it can demonstrate the safety of their drugs.
As implied by the title of the guidance, Evaluating Drug Effects on the Ability to Operate a Motor Vehicle, the document is concerned with driving impairment and how manufacturers of psychoactive drugs—not just sleep aids—should assess their drugs' effects on a patient's ability to drive.
As FDA explains in its guidance, a drug's effects on driving can sometimes be varied. "In some cases, psychoactive drugs might appear to have the potential to improve driving performance, for example by decreasing somnolence (an established risk factor in MVAs)," FDA wrote. "However, drugs can have additional effects that increase the likelihood of driving impairment; for example, CNS stimulants might increase risk-taking."
FDA said it would in many cases recommend "driving studies" to determine if a drug has an effect on a patient's ability to operate a motor vehicle. Studies would also be required if a drug was submitted at a higher dose, a different dose schedule, for a different indication or in a new patient population, FDA said. That could add yet another hurdle to bringing central nervous system (CNS) drugs—already one of the most difficult types of drugs to develop—to market quickly.
A Tiered Approach and Driving Studies
FDA's guidance goes on to call for a "tiered" approach to evaluating how drugs affect driving. FDA says drug effects should be measured in the following five areas:
- Attention and processing speed
- Reaction time/psychomotor functions
- Sensory-perceptual functioning
- Executive functions
FDA's guidance also calls for some sponsors to conduct dedicated driving studies with the use of either real vehicles or driving simulators. However, FDA said that these studies should not use motor vehicle accidents (MVA) as an endpoint, calling it "unethical."
"Instead, studies that assess the effects of a drug on CNS functions necessary for safe driving should be used to assess the potential for causing MVAs," FDA said.
Driving studies should, in general, include a control group and placebo group, and include patients who "Are from the population likely to use the drug," such as the elderly. Patients should also be dosed with the higher exposure expected to be used in a clinical study, FDA said.
Added FDA: "Driving impairment cannot be fully defined by any single domain, such as alertness; however, evidence of clinically meaningful impairment of even a single domain may be sufficient to conclude that the drug impairs driving, and may provide an adequate basis for regulatory action."
Companies should also take note of a drug's pharmacologic properties, epidemiological data about adverse events, and data from clinical studies that might indicate potential effects on driving.
Evaluating Drug Effects on the Ability to Operate a Motor Vehicle (FR)