Silvia Zaragoza Domingo

During 2023, the leads of the ECNP TWG focused on Clinical Outcomes in Early-Trials in Neurosciences scheduled two brainstorming sessions to allow a deep discussion about challenges facing neurosciences drug development in neuropediatric rare diseases. Sessions were led by Dr Maria T. Acosta from the Undiagnosed Disease Program (UDP) at the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, EE.UU. The experts discussed about challenges and potential solutions as well as alternative options to design appropriated for clinical outcomes assessment (COA) instruments for this population. An important discussion took place due to extensive expertise of the participants and hands-on experience with clinical trials. Participation from experts from several disciplines was a key factor for appraising and brainstorm innovative solutions in the field. Identification of challenges and propose of innovative solutions were a central core of the discussion. Despite of the increasing number of rare and ultra-rare diseases being identify by the day, and the significant differences in biology, and clinical presentation, it is clear most of them face similar problems when is time to select the appropriated COAs to test potential interventions, and experts have a limited potential to drive efficient solutions. Some of the commonly identified common problems include: small number of patients affected, disease changes over time, developmental aspects impacting the clinical presentation according with age, individual variability in terms of disease severity between patient, variable window for intervention and in some cases, need to expedite treatment as per the disease progression. All these and other features, require an extensive dialogue and continue communication between preclinical researchers, clinicians, patients and family members, pharma and treatment designers and regulatory agencies in each condition, making this process, expensive, time consuming and very difficult to accomplish. A feasible solution, that may be applicable to several conditions, is to develop a “back bone” structure to approach rare diseases, allowing each “disease team” to tailored assessments and study design, according with the specific features of the condition. We concluded that it is fundamental to establish effective bridges of communication between the different actors implicated in the clinical trial design and execution, sharing experiences, as well as clear understanding of meaningful outcomes not only for researchers, but clinicians, patients and families. Important emphasis is done in the need or careful selection of COAs in each individual condition to be able to obtain more efficient and reliable results in clinical trials in this population. We need to be creative, and there is a need to leave the “comfort zone” of current methodologies and start piloting new methods at clinical settings. A specific research platform was proposed as a solution in the creation, sharing and validation of new assessment instruments, which would be available to clinicians and researchers attending small patient samples distributed over the world.

Background: Clinical trials for rare diseases pose unique challenges warranting alternative approaches in demonstrating treatment efficacy. Such trials face challenges including small patient populations, variable onset of symptoms and rate of disease progression, and ethical considerations, particularly in neurodegenerative diseases. In this study, we present the retrospective clinical global impression (RCGI) severity and change (RCGI-S/C) scale on 27 patients with GM1 gangliosidosis, a post hoc clinician-rated outcome measure to evaluate natural history study participants as historical controls for comparisons with treated patients in a clinical trial. Methods: We conducted a systematic chart review of 27 GM1 gangliosidosis natural history participants across 95 total visits. RCGI-S was assessed at the first visit and rated 1 (normal) to 7 (among the most extremely ill). Each subsequent follow-up was rated on the RCGI-C scale from 1 (very much improved) to 7 (very much worse). We demonstrate scoring guidelines of both scales with examples and justifications for this pilot in GM1 gangliosidosis natural history participants. The convergent validity of the RCGI scales was explored through correlations with magnetic resonance imaging (MRI) and the Vineland Adaptive Behavioral Scales. Results: We found strong association between the RCGI-S scores with gray matter volume (r(14) = −0.81; 95% CI [−0.93, −0.51], p < 0.001), and RCGI-C scores significantly correlated with increases in ventricular volume (χ²(1) = 18.6, p < 0.001). Baseline RCGI-S scores also strongly correlated with Vineland adaptive behavioral composite scores taken at the same visit (r(14) = −0.72; 95% CI [−0.93, −0.17], p = 0.02). Conclusion: RCGI-S/C scales, which use the clinical evaluation to assess the severity of disease of each patient visit over time, were consolidated into a single quantitative metric in this study. Longitudinal RCGI-C scores allowed us to quantify disease progression in our late-infantile and juvenile GM1 patients. We suggest that the retrospective CGI may be an important tool in evaluating historical data for comparison with changes in disease progression/mitigation following therapeutic interventions.

Clinical trials for rare diseases pose unique challenges warranting alternative approaches in demonstrating treatment efficacy. Such trials face challenges including small patient populations, variable onset of symptoms and rate of disease progression, and ethical considerations, particularly in neurodegenerative diseases. In this study, we present the retrospective clinical global impression (RCGI) severity and change (RCGI-S/C) scale on 27 patients with GM1 gangliosidosis, a post hoc clinician-rated outcome measure to evaluate natural history study participants as historical controls for comparisons with treated patients in a clinical trial. We conducted a systematic chart review of 27 GM1 gangliosidosis natural history participants across 95 total visits. RCGI-S was assessed at the first visit and rated 1 (normal) to 7 (among the most extremely ill). Each subsequent follow-up was rated on the RCGI-C scale from 1 (very much improved) to 7 (very much worse). We demonstrate scoring guidelines of both scales with examples and justifications for this pilot in GM1 gangliosidosis natural history participants. The convergent validity of the RCGI scales was explored through correlations with magnetic resonance imaging (MRI) and the Vineland Adaptive Behavioral Scales. We found strong association between the RCGI-S scores with gray matter volume (r(14)=-0.81; 95% CI [-0.93, -0.51], p less than 0.001), and RCGI-C scores significantly correlated with increases in ventricular volume (𝜒2(1)=18.6, p less than 0.001). Baseline RCGI-S scores also strongly correlated with Vineland adaptive behavioral composite scores taken at the same visit (r(14)=-0.72; 95% CI [-0.93, -0.17], p=0.02). RCGI-S/C scales, which use the clinical evaluation to assess the severity of disease of each patient visit over time, were consolidated into a single quantitative metric in this study. Longitudinal RCGI-C scores allowed us to quantify disease progression in our late-infantile and juvenile GM1 patients. We suggest that the retrospective CGI may be an important tool in evaluating historical data for comparison with changes in disease progression/mitigation following therapeutic interventions.