Rare Diseases Often Lack CGI-Specific Scales
Rating scales such as the Clinical Global Impression-Severity (CGI-S) and the CGI-Improvement (CGI-I) allow physicians to assess overall symptom severity and improvement in patients with neuropsychiatric disorders. These assessment tools quantitatively summarize the clinician’s impression of the patient’s global state and frequently serve as outcome measures in clinical trials. Disease-specific rating scales often accompany the CGI-S and CGI-I but have been unavailable for some rare diseases, such as Angelman syndrome (AS).
Dr. Pamela Ventola, Cogstate’s Senior Science Director for Rare Disease and Pediatrics, highlighted the challenges associated with outcome measures in rare disease: “Individuals with a rare disease are often quite heterogeneous in their clinical presentations. Further, many individuals with rare disorders are highly impaired so that even incremental changes have substantial impacts on functioning and quality of life. Outcome measures in rare disease need to account for both this heterogeneity and also be sensitive enough to detect small changes.”
A Rigorous Approach to Develop a Standardized CGI Scale for Angelman Syndrome
A research team including Dr. Ventola embraced this challenge and created the CGI-S/-I-AS, an adapted rating scale that specifically quantifies AS symptoms. A study published in the Journal of Developmental Disorders describes in detail the systematic 5-step process that resulted in the development and validation of the CGI-S/-I-AS scale. When implemented along with rigorous training and calibration, this new reliable scale will positively impact AS clinical trials, as it can reliably assess treatment efficacy.
AS Critical Domains and Rating Anchors
In the first two steps of the development process, investigators conducted an extensive literature review and interviewed key stakeholders (caregivers and clinicians) to identify the most important AS symptoms domains. Expert clinicians analyzed the results and identified six symptom categories: behavior, fine motor, gross motor, expressive communication, receptive communication, and sleep.
Next, the research team developed rating anchors that accurately reflect symptom severity for each symptom domain. Severity related to the impact on the individual’s overall functioning of and quality of life. The final rating scale had seven levels of severity ranging from 1 (normal) to 7 (extremely impaired).
CGI-S/-I-AS is a Reliable and Clinically Meaningful Rating Scale
Investigators conducted a second round of interviews to identify the minimum symptoms changes in each domain that would qualify as clinically meaningful. Based on the feedback of care providers and clinicians, researchers identified that a CGI-I score of 3 in all the domains would indicate a minimal but significant improvement. The CGI-I is sensitive enough to detect a moderate (score of 2) and marked (score of 3) improvement in the symptoms.
Finally, the research team used the finalized CGI-S/-I-AS scale to conduct mock patient interviews, train raters, and determine the scale inter-rater reliability. Analysis revealed that CGI-S/-I-AS is sensitive and has a good to excellent reliability between raters. Also, changes over time are not due to differing perspectives from caregivers but indicate an actual sensitivity to detect improvement in symptoms.
A Novel Rating Scale to Advance Clinical Trials
The CGI-S/I-AS is novel and highly relevant to clinical practice and trials. It emerged to fill the need for a reliable and validated outcome measure in a rare neurodevelopmental disorder such as Angelman syndrome. Commenting on the impact that CGI-S/I-AS will have on future clinical trials, Dr. Ventola said:
“The CGI-S/I-AS is both sensitive enough to detect small changes and also accounts for the heterogeneity of clinical presentation in the AS population. As such, the measure is highly impactful and will support significant advances in clinical trials and measurement of change in individuals with AS.”