The Promise of Technology for Clinical Development
The use of digital biomarkers in clinical development holds the promise of delivering huge value by creating operational efficiencies while enabling more sensitive, more expeditious, and more informed decisions. In order to enable clinical decision making, information must by definition be clinically relevant which requires validation of the measures and consensus on what is deemed relevant by experts in the field. Claims regarding the usefulness of digital biomarkers should be based on demonstrated analytical validity, especially if digital biomarkers are to be used as primary or secondary endpoints in clinical studies.
Cognitive impairment is a cardinal feature of many neurological diseases and seriously impacts a patient’s quality of life. Traditionally, complex and lengthy neuropsychological batteries are administered by medical specialists. More recently, significant progress has been made in developing user friendly scientifically validated instruments for cognition assessment that utilize digital technology (1-6). These assessments measure processing speed, executive function, episodic memory and cognitive interference. The digital tests are engaging and portable.Some have the potential to be scaled for use beyond the clinical trial setting (1-3) and a number have FDA clearance, or are on track to get FDA clearance, for use as medical devices.
One of the real challenges in the field of cognition assessment is the desire to measure small deficits early in the disease process, to enable the design of clinical trials in early stages of neurodegenerative disease. The belief is that technology can be used to create sensitive and precise measures, but whether they can be accurate predictors of disease progression has not yet been fully proven.
Rigorous Scientific Validation
Through the application of rigorous science and clinical validation, even the most non-traditional measures can become highly precise and clinically informative outcome measures, which can be used in novel and creative ways. Akili Interactive exemplify this in their disciplined approach to developing their EVOTM platform, a closed loop video gaming platform used as a neurological assessment tool and for brain training (2). This company has proven that game-based tools promote neuroplasticity, train the brain to improve cognitive function, and can also be used as sensitive and precise measures of cognitive ability.
Through thorough clinical validation investigators at the Cleveland Clinic have shown that a digital version of an established clinical endpoint, the symbol digital modalities test (SDMT), can be quickly self-administered by patients with high test-retest reliability and is a sensitive measure of cognitive dysfunction in MS patients (2).
Understanding the Context of Use
Critical to the process of validation is understanding the intended use of the measure and what claims can be made as a result of using a particular measure. Only then can the measure be demonstrated to be reliable, sensitive and predictable, and the results interpreted with clinical meaning. For cognitive assessment, scientific validation is grounded in classical test theory requiring traditional stages of validation, demonstration of reliability and relevance in the disease group of interest. These same principals of validation have been applied to biologic, psychological and PRO measures previously. Validation steps like these will enable the use of digital assessment tools in clinical trials as primary or secondary endpoints. Regulatory science is certainly moving in this direction as policy drivers, such as the Critical Path Institute, address how we as an industry set standards and inform guidelines to qualify digital biomarkers (7).
Senior Director, New Initiatives
Value Based Medicine Innovation Hub
- Mishra J, Anguera JA, Gazzaley A. (2016) Video Games for Neuro-Cognitive Optimization Neuron
- Rao S, Mourany L, Schindler D, Mamone B, Reece C, Kemeny D, Narayanan S, Miller D, Bethoux F, Bermel R, Rudick R. (2017) Processing Speed Test: Validation of a self-administered, iPad-based tool for screening cognitive dysfunction in a clinical setting. Multiple Sclerosis Journal In Press