COGNITION IN CLINICAL PHARMACOLOGY STUDIES:
examining both simple cognitive domains and complex cognitive tasks such as driving
As a sponsor, why would I want to add cognition testing to my First-in-Human (FIH) program?
It is important to note that the FDA Guidance states that “sponsors can use drug information obtained early in development to guide the need to collect data later in development related to driving impairment potential” without directly specifying the need for such assessments in FIH studies. However, from our experience, adding cognitive testing to FIH studies can provide valuable insight because FIH studies have a few elements that make them ideal for assessing the cognitive effects. First, FIH are conducted in a confined setting, where all key elements are controlled, which helps reduce the variability caused by external variables. Also, FIH studies are conducted with ascending single doses then with ascending multiple doses with extensive pharmacokinetic sampling, giving invaluable dose and concentration response data. As an example, we have seen instances where with multiple doses cognitive effects are observed on the first dose, but within a few days, tolerance is developed. We have also seen cases where the cognitive changes last for hours after the drug is eliminated from the blood, a very important detail to understand for later clinical development. Finally, the cognitive testing can also be included to provide an extra level of safety in case there are neurocognitive changes that would otherwise go undetected. Adding formal evaluations in early stage trials aligns with the guidance’s point that patients cannot always be relied on to self-report issues. Particularly with cognitive effects, they may not even recognize that a change has occurred. These evaluations can also be very helpful in de-risking subsequent trials, and providing additional support when deciding whether a dedicated driving study may be required.
My company is currently in Phase II development of a novel pain medication. How do we find out if and when we need to perform a driving study? And when do most companies make that decision?
If unsure, it is always best to speak and confirm with a regulatory agency or a qualified CRO, such as Altasciences or Cognitive Research Corporation. For pain medications, such as for migraines, driving studies are likely to be required as they are often associated with sedation or potential impairment. Typically, these are completed in late phase II. We have worked with a number of sponsors who were asked by the FDA to conduct driving studies at the end of Phase II Meeting.
If we are repurposing a drug, changing the formulation slightly, would we still need to perform a dedicated study? Could we opt to use the current labeling of the marketed product?
You might, depending on regulatory requirements and whether the pharmacokinetics of the compound change, especially if the exposure if increased. You may also want to perform cognition studies even if not required by regulatory agencies… here’s why: label claims. Many sponsors are looking to soften labels from older drugs to show their drug is safer than other drugs on the market; e.g., easier dosing schedules, morning after effect of the drug. There are many drugs on the market that were approved prior to any formal driving studies being performed, and their labeling may be based on post-marketing reports or other less rigorous observational studies. Many of the sponsors we work with are aiming to have the warnings about cognitive effects, such as to not operate heaving machinery, removed or reworded from the label of their repurposed product.