Behavioral and Biological Markers in Rare Disease Research: Tandem Approach Increases Sensitivity and Specificity

March 1, 2022

Clinical trial teams are seeking to increase sensitivity and specificity in their rare disease research by both developing indication-specific behavioral measures and leveraging biological markers of treatment response.

At the recent Neurodevelopmental Disorders Drug Summit, Dr. Pam Ventola (Associate Professor, Yale & Senior Science Director, Cogstate), and Dr. Kevin Pelphrey (Professor, University of Virginia), presented research on behavioral and biological measures, and described considerations for using these measures in tandem to more precisely identify cognitive and/or behavioral variation. 

Developing Indication-Specific Behavioral Measures

At a minimum, assessments in rare disease trials should be appropriate for the functioning level of the population and have adequate sensitivity and specificity to detect change over time in the target population. However, the presenters acknowledged this can be difficult to achieve utilizing only common assessment options.

“Having spent many years designing, conducting, and consulting on clinical trials in rare disease, I’ve seen how the clinical assessments selected for the study greatly impact the ability to tell a conclusive story about treatment benefit,” said Dr. Ventola. “There is a growing need for the development of indication-specific outcome measures for rare disorders.”

Indication-specific measures enable more granular detection of changes in cognition or behavior and are often proximal to the target mechanism/domain the drug or therapy is thought to change. In line with this need, Dr. Ventola described how researchers are beginning to adapt well-accepted measurement tools from other indications for use in rare and neurodevelopment disorder trials such as the Clinical Global Impressions Scale (CGI), Visual Analogy Scale (VAS), and the Caregiver Impressions of Change Scale.

When developing indication-specific outcome measures, researchers should consider:

  • source of information (caregiver report, patient report, observations of patient, psychometric scores, etc.),
  • granularity of ratings
  • content of ratings
  • anchors
  • comparison group
  • and timeframe for rating

Examples of indication specific outcome measures include Rett Syndrome Behaviour Questionnaire, Unified Batten Disease Rating Scale, and Sanfilippo Syndrome Rating Scale.

[NORD Poster Describes Development of Indication-Specific Outcome Measure for Fragile X]


Developing Biological Biomarkers (Case Study: Autism)

In addition to the use of indication-specific outcome measures, researchers are working on the development of more precise biological markers. As an example, Dr. Ventola and Dr. Pelphrey shared data from their work on new approaches in autism.

Dr. Ventola noted researchers have looked at the function of the brain (via MRI) to understand mechanism of action. “If there is a structural abnormality that goes along with a developmental disability or rare disease this can generally be detected early. In a case like autism, the structure of the brain is fine; the issue is how the brain is functioning.”

Using a scanner, measurements can be taken to see which part of the brain is getting more blood flow. This indicates which part of the brain is working and is known as Activation. For example, if you’re speaking, the part of your brain involved with production of language gets more blood flow.

This method, known as Pivotal Response Treatment, was used in a clinical trial of a treatment for pediatric autism spectrum disorder. Before and after treatment, the children completed an fMRI where they watched a biological motion paradigm and non-biological motion. (See the videos at the end of the blog.)

The “Coherent Biological (BIO)” video makes human-like movements, even though it’s just a set of dots. The control condition video is called Scrambled Biological (SCRAM), where the dots are very closely controlled in terms of speed and relation to each other but is not considered biological motion.

Researchers assessed the differential activation between the two conditions, separating brain activation in response to social information. Dr. Ventola said, “we found significant improvement in behavior and social communication. Also, importantly we found a biological marker of treatment response with increased activation in areas of brain associated with social processing.”

At this point, it is not possible to do a scan of an individual and make a prediction on whether an individual will have autism or not. Researchers are hopeful that more assessments can be made at the individual level so these methods can be used towards diagnostic sensitivity, particularly early in development and for other indications.

Considering this process as it relates to the development of new therapeutics, Dr. Ventola noted:

The measures used in all types of CNS clinical trials are relatively distal to the brain. If you take a drug, it changes your brain. We’re not measuring the brain change. We’re measuring the downstream effects of that brain change. We try to get this as proximal as we can, but we’re still measuring memory, speed of processing, or attention as an outcome to brain change. We want to tie these together and to get closer to get early efficacy indicators. If you start a treatment that’s either expensive or invasive, it would be ideal to know if it’s starting to work before you continue until the point where you can measure change.”

Correlating Biological and Behavioral Markers in Clinical Trials 

Leveraging both biological and behavioral measures in rare disease and neurodevelopmental trials can provide helpful data for better decision making on the safety and efficacy of a drug. Furthermore, regulators are increasingly asking and expecting pharmaceutical teams to provide data on therapeutic candidates showing correlation between behavioral and biological changes.

In taking this tandem measurement approach, researchers must ensure the biological and behavioral measures are synergistic. Measurements could be gathered from an anatomical fMRI and from a social functioning scale, but the two might not correlate at all. This will make it look like a study failed when it didn’t. Another common approach is to use eye tracking as the biological marker. But without distinct planning as to what will be measured with eye tracking and what the subjects will look at, the data becomes unusable.

Cogstate’s scientific experts understand the nuances of both behavioral and biological markers and can help your team determine an approach that will be effective and efficient. We invite you to contact us or check out resources here on how we support rare disease trials to learn more.

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