We're getting ahead of ourselves...
“The most elegant design of a clinical study will not overcome the damage caused by unreliable or imprecise measurement.” --Joseph L. Fleiss
In the last few years, researchers have made tremendous advances in CNS therapies. For the first time in decades, we’re developing drugs with new mechanisms of action. Unfortunately, our measurement tools are stuck in the past.
A new era
The last time we had a completely novel mode of action in a CNS therapy, it was with risperidone in the ’90s--and the early ’90s at that. Study of this atypical antipsychotic began in the late 1980s; it was approved for sale in the United States in 1993. Before that, we had Prozac and the SSRIs.
It’s been a while, but here we are again, this time with rapid-acting antidepressants. Ketamine and related compounds hold the promise of fast, novel and effective treatment of depression. These rapid-action antidepressants can take effect in a matter of hours.
Even with SSRIs such as Paxil or Prozac, it can take six weeks before patients experience any meaningful effect. The new medications often take hours. We’ve seen this in suicidality studies: A patient comes to the emergency department with suicidal thought, receives the medicine and the suicidality resolves within a few hours.
That completely changes the depression paradigm, and it sounds amazing. Strike that: It is amazing. But there’s a catch: We don’t have the appropriate measurement tools.
All the current depression scales for antidepressants were created in the era of old-school, slow-acting antidepressants.
A ham-fisted tool
Consider the Ham-D. It was developed in 1960 and is still used today. Its questions, such as “How has your sleep been in the last week? How has your appetite been in the last week?” still have tremendous value. It has its place. However, it was designed to be administered once every two weeks, maybe six times over the course of the trial.
But we aren’t talking weeks for these new antidepressants. Researchers are using a set of questions designed to detect changes over weeks to detect changes over a few hours.
Imagine asking a woman who's just given birth, “How's your sleep been over the last week?” She’ll probably be annoyed and say something like, “Really?! I was nine months pregnant last week. I just gave birth today, so not that great.” And then four hours later saying, “Okay, what about now? How has your sleep been over the last week?” You get the picture.
And here’s another catch: Some of these rapid-acting medications may not work over the long term in some patients. This means the current tools don’t do a good job of measuring the immediate effect, and what they do measure--a longer-term impact--may not even matter.
The science has changed so much from when the Ham-D was first published. It’s like using one of those huge mobile phones from the 1980s and trying to get service now.
So how do you get a signal? Get a new phone.
Similarly, we need sensitive instruments that we can administer multiple times over the course of hours--and detect change.
This isn’t a new concern, of course. Back in 2015, researchers looked at several depression scales and determined that individual items from some of them may be suited to assessing rapid changes in suicidal thoughts. It’s better than nothing, but ultimately, it’s an unsustainable piecemeal approach.
We need to develop better ways to measure. We need 21st-century tools.
No, you go first
No one wants to be the first to change an outcome measure. It’s a resource-intensive process, involving very specific pathways at the FDA. But eventually, sponsors need to get this changed. They need a better way to measure, and they don’t want the burden of handling it in house.
That’s why they are turning to our experts.
WCG MedAvante-ProPhase has been involved in all the rapid-acting antidepressant trials to date, so our experts know what works. For instance, they can suggest approaches that were initially designed for a different class of drugs. This requires deep clinical expertise but, ultimately, it’s operational.
Our experts give advice based not on conjecture, but on how they have made those adjustments themselves. Many have run similar trials as principal investigators. They understand the nuances of the available measurement tools and the implications on both the operational and clinical sides.
This expertise--which marries science with practical experience--will be essential as research advances. It’s not just depression: We expect tremendous strides in ADHD, bipolar disorder and other CNS areas. Measurement tools must keep pace with the research. Ideally, it should be a few steps ahead.
We can help. CNS--and specifically, measurement science in CNS--is all we do. We have the experts, the expertise and the experience.
 Fleiss JL. The Design and Analysis of Clinical Experiments. New York: Wiley; 1986.