Cognitive Guidance for Clinical Drug Trials

The FDA has shown an increased sensitivity to the sedating and impairing effects of drugs. Since 2013, the agency has issued warnings or taken action on dosage recommendations across the therapeutic spectrum, ranging from approved hypnotics (e.g., Ambien, Lunesta) to over-the-counter antihistamines. The focus has mainly been on driving safety.

Drugs that stimulate or depress CNS functioning have the potential to impact driving safety. As new drugs enter the approval process, the FDA is increasingly requesting an assessment of the their potential to impair driving. In the past, the focus was on drugs that target CNS function such as hypnotics and antidepressants. It is now recognized that drugs whose primary therapeutic activity is not CNS, such as antihistamines and antispasmodics, can also impair driving. We are awaiting guidelines from the FDA that will lay out the standards for conducting the studies needed to evaluate if a drug impairs driving. How can pharmaceutical manufacturers prepare for this new guidance?

Obviously, drugs known to produce somnolence will be required to undergo a thorough assessment of their potential to impair driving. However, it is also critical to assess drugs that impair attentional abilities such as concentration, divided attention, or selective attention. Drugs that interfere with psychomotor speed or coordination are a cause for concern, too, as well as those that impair executive functions (e.g., judgment, planning). Unfortunately, we can't rely on self-reported sedation to identify those drugs that can potentially impair driving performance.

The recommendations of the National Highway Transportation Safety Administration (NHTSA) panel evaluating drug impaired driving (http://www.nhtsa.gov/staticfiles/nti/pdf/811438.pdf) are likely to be a model for FDA guidance. The protocol identifies the essential driving ability domains (cognitive and psychomotor) and identifies tests for assessing these domains. The report discusses the role of standardized cognitive and psychomotor tests, driving simulation, and over-the-road driving tests.

For many years, studies were conducted in Europe using an instrumented car on an active highway. This method was effective for measuring weaving but failed to provide a measure of other abilities essential to driving. This type of over-the-road testing appears likely to be eclipsed by driving simulation as demand for driving studies increases.

Historically, driving simulator studies conducted at a limited number of research sites employed a single driving simulator that used custom software and driving scenarios unique to that site. These simulators had not undergone the software validation or data validation required for a regulatory study.

Advanced driving simulators, however, provide realism and driver immersion, along with a standardized and validated platform for testing drug-impaired driving. CRC MiniSim, for example, uses a standardized chassis with a full-size car seat, steering wheel, and pedals. The driving scene is presented on three monitors, roughly the size of a car windshield. Driving scenarios have been validated with respect to their sensitivity to the effects of drugs and alcohol. In order to conduct multicenter clinical trials, a fleet of these simulators have been developed and deployed to sites in the U.S., Canada, and Europe. For example, our group recently completed a study employing nine of these simulators in a protocol that tested the acute and steady-state effects of a potentially sedating medication at multiple doses, compared to placebo and an active control.

The technology and methodology is now available to meet the expected regulatory demands for assessing the potential for drugs to impair driving. Pharmaceutical companies can begin to prepare for upcoming FDA guidance on evaluation of drug-impaired driving.

Gary G. Kay, PhD President, Cognitive Research Corporation. E-mail: [email protected]