The Long Curve Behind CNS Drug Testing

In the past week, I’ve had two interviews and one webinar all related to some form of safety measuring and diagnosis definition primarily in the CNS area. The Impact of Non-Restorative Sleep for Mental Health Definition, Diagnosis, Evaluation, Treatment and Clinical Trials webcast; and interviews with Gary Kay, PhD, president of Cognitive Research Corporation about advances in his driver simulation technology for clinical trials; and Lynn Webster, MD, chief medical director for early phase clinical research company CRI Lifetree, who discussed Human Abuse Liability testing and the changes industry is facing in regard to conduct in trials of drugs that contain molecules or formulations that are potentially abusive.

You have to stick with me here on my observations because I’m still in the formulating stage. So feel free to share your specific experiences or thoughts with me, but there are similarities:

• Each one of the experts I listened to has extensive knowledge and leadership in their specific area

• Each points to the need for sponsors to be aware of recent FDA guidance or potential guidance coming their way

• The need to address comorbidities and/or combined drug effect potential in drug evaluation, as well as subject recruitment

• Earlier identification of potential problems with drugs in trials

Dr. Kay developed the miniSim driving simulator that can evaluate consistently the impairment level of drivers. Instead of driving an actual car on a closed course, which is difficult to replicate across trials, and is not really safe when you think about it, the simulator can evaluate a person’s cognition in relation to driving in sleep studies, pain studies, and other drugs that may impair driving. Even so far as to next-day affects, which was recently the case with Ambien’s dosing change in women. A women’s metabolism of the drug turned out to be much slower than a men’s, so next day impairment became a factor.

Tie that in with Dr. Thomas Roth of the Henry Ford Hospital Sleep Center, who presented that the effects of non-restorative sleep (NRS) become apparent in a person’s role functioning. Apparently NRS causes a significant increase in daytime sleepiness, as well as reduced quality of functioning, and an increase in days out of role due to that problem. Sleep scores and how to achieve them accurately was described by Dr. Roth, who also admitted more research needs to be done in sleep disorders, as well as in evaluation of drugs that not only help people sleep, but keep them awake.

Then enter Dr. Webster’s formidable expertise in the testing of human abuse liability. Dr. Webster was recently elected president of the American Academy of Pain Medicine, and shared with me that there has been a definite shift of sponsors conducting HAL studies from end of Phase III to Phase I and Phase II. “It helps with making decisions in how to design their Phase III trials and how to position the drug in Phase III,” explained Webster. HAL studies also are intensely evaluated, akin to a Phase I trial, in that they are conducted in-house for three to six weeks. Meanwhile, the evaluation of abuse potential is a balance of subjective and objective measures. While most of the endpoints lie in the subjective, more objective measures include pupillometry and PK/PD studies. But determining the “liking” effect--that is the subjects potential to feel not only euphoria, but also sedation or hallucination—falls into the scales and patient-reported area, much like how people are graded on their sleep disorder.

So my observation is that, we are coming to a more patient-centric way of developing drugs. Probably, realistically patient-reported outcomes are the first usable determinant of subjective measures in clinical trials for numerous conditions. Patient reported outcomes are also more important now for pharmaceutical companies in the ability to quantify one drug’s improvement of quality of life, or other subjective measures over another on the drug’s labeling. And obviously, this could effect reimbursement.

In the end, the regulatory authorities want a drug that balances safety and efficacy as much as possible. In determining what safe is, it seems that we are evolving to another level of science. That is, yes “x” may be a side effect of the drug you are taking, but in all likelihood, it could make you addicted, make you likely to drive as impaired as someone with a high blood alcohol level or your condition could make you unable to work for two days a month. But all measures and data collected in a clinical trial, as was recently explained to me, is an outcome. Finding and measuring those scientific nuances, as knowledge grows, is an art.