Commonalities and Challenges in the Development of Clinical Trial Measures in Neurology

Abstract

As neurologists and neuroscientists, we are trained to evaluate disorders of the nervous system by thinking systematically. Clinically, we think in terms of cognition, behavior, motor function, sensation, balance and co-ordination, and autonomic system function. But when we assess symptoms of neurological disorders for the purpose of drug development, we tend to create disease-specific outcome measures, often using a variety of methods to assess the same types of dysfunction in overlapping, related disorders. To begin to explore the potential to simplify and harmonize the assessment of dysfunction across neurological disorders, a

Sample enrichment for clinical trials to show delay of onset in huntington disease

“…Based on current knowledge of premanifest natural history, measures of disease progression are often nonlinear, particular to one component or phase of the disease, and reflect wide variability secondary to heterogeneity. Although searches for new biomarkers and refined clinical markers are beneficial (and necessary), currently available candidates are not US Food and Drug Administration (FDA) qualified or psychometrically validated for implementation in prodromal HD . Preventive treatments in prodromal participants delivered using outcomes that have not yet been vetted to demonstrate robust intra‐ or interrater reliability, cross‐site reliability, or cross‐platform reliability (in the cases in which imaging scanners or computers are involved) or not yet validated with participant‐reported or meaningful outcomes could challenge interpretation of findings.…”

“…Clinical trial successes in CNS disorders are primarily symptomatic treatments . Disease‐modifying interventions face a number of challenges . One significant limitation of disease modification trials is the assumption that intervention(s) effective at one stage of a disease are equally applicable at other points in the disease course, yet many evidence‐based treatment guidelines vary by disease stage, risk, and severity.…”

Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic

“…Understanding the clinical meaningfulness of the effects of “symptomatic” medications such as levodopa and dopamine agonists in PD is fairly straightforward because of the rapid and dramatic nature of the clinical response. However, for agents aimed at slowing PD progression, not necessarily associated with short‐term clinical improvement, detecting a clinically meaningful effect presents a significant challenge because of the slow rate and variability of the progression of symptoms between individuals . In this setting, the use of biomarkers to select and stratify patient populations, as well as to document biological effects of candidate drugs, assume critical importance in the drug development efforts.…”

“…However, for agents aimed at slowing PD progression, not necessarily associated with short-term clinical improvement, detecting a clinically meaningful effect presents a significant challenge because of the slow rate and variability of the progression of symptoms between individuals. 93 In this setting, the use of biomarkers to select and stratify patient populations, as well as to document biological effects of candidate drugs, assume critical importance in the drug development efforts. The availability of large, prospective natural history datasets that contain detailed clinical, imaging, genetic, and fluid biomarker data is key to efforts to develop disease-modifying therapies for PD, just as the Alzheimer's Disease Neuroimaging Initiative has so well served the cause of drug development for Alzheimer's disease.…”

AlzheimerÂ’s and ParkinsonÂ’s Diseases Face Common Challenges in Therapeutic Development: Role of the Precompetitive Consortium, Coalition Against Major Diseases

“…Working in pre-competitive space, the team achieved consensus on an approach to qualification, which enabled them to leverage resources and potentially increase the efficiency of future studies [18]. Regulators noted that qualification is only one pathway to approval of a drug development tool, and in some cases it may be quicker for sponsors to work independently through the Investigational New Drug (IND) review process.…”