Design and Statistical Innovations in a Platform Trial for Amyotrophic Lateral Sclerosis.

Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products in parallel and sequentially in persons with amyotrophic lateral sclerosis (ALS) with the goal of rapidly identifying novel treatments to slow disease progression. Platform trials have considerable operational and statistical efficiencies compared with typical randomized controlled trials due to their use of shared infrastructure and shared control data. We describe the statistical approaches required to achieve the objectives of a platform trial in the context of ALS. This includes following regulatory guidance for the disease area of interest and accounting for potential differences in outcomes of participants within the shared control (potentially due to differences in time of randomization, mode of administration, and eligibility criteria). Within the HEALEY ALS Platform Trial, the complex statistical objectives are met using a Bayesian shared parameter analysis of function and survival. This analysis serves to provide a common integrated estimate of treatment benefit, overall slowing in disease progression, as measured by function and survival while accounting for potential differences in the shared control group using Bayesian hierarchical modeling. Clinical trial simulation is used to provide a better understanding of this novel analysis method and complex design. ANN NEUROL 2023;94:547-560.

Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers. METHODS: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration. RESULTS: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing. DISCUSSION: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.

Adaptive Platform Trials to Transform Amyotrophic Lateral Sclerosis Therapy Development.

Current therapeutic development in amyotrophic lateral sclerosis (ALS) relies on individual randomized clinical trials to test a specific investigational product in a single patient population. This approach has intrinsic limitations, including cost, time, and lack of flexibility. Adaptive platform trials represent a novel approach to investigate several interventions for a single disease in a continuous manner. Already in use in oncology, this approach is now being employed more often in neurology. Here, we describe a newly launched platform trial for ALS. The Healey ALS Platform Trial is testing multiple investigational products concurrently in people with ALS, with the goal of rapidly identifying novel treatments, biomarkers, and trial endpoints. ANN NEUROL 2022;91:165-175.

Expanded access protocol (EAP) program for access to investigational products for amyotrophic lateral sclerosis (ALS).

INTRODUCTION/AIMS: Expanded access protocols (EAPs) are a Food and Drug Administration (FDA)-regulated pathway for granting access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. There is limited information about the use of EAPs in amyotrophic lateral sclerosis (ALS); the aim of this report is to share the design, operational features, and costs of an EAP program for ALS. METHODS: The program was launched in 2018 at a single center. In alignment with FDA guidance, protocols were designed as individual (single participant) or intermediate size. Inclusion criteria were broad (e.g., no restrictions due to long disease duration or low vital capacity). Safety information was collected in all EAPs. Selected biomarkers were collected in nine of the EAPs. RESULTS: From July 2018 through February 2022, 17 EAPs were submitted for FDA and institutional review board (IRB) approval. The mean time from submission to approval from the FDA and IRB were 24 days and 37 days, respectively. A total of 164 participants were enrolled and, of these, 77 participants were still receiving IP as of February 2022. The mean duration of participation in an EAP was 12.6 mo. No drug-related serious adverse events were reported from any of the EAPs. Average site cost was $613.47 per participant per month, not including IP costs. CONCLUSION: EAPs provide a framework through which access to IP can be safely provided to people with ALS who do not qualify for clinical trials. Site resources are needed to launch and maintain these programs.

Adjusted cost analysis of video televisits for the care of people with amyotrophic lateral sclerosis.

INTRODUCTION: We previously reported our amyotrophic lateral sclerosis (ALS) video televisit experience. Here we report on video televisit versus in-clinic costs, adjusting for perceived medical usefulness (MU). METHODS: We take the patient-perspective and a focused institutional-perspective. Costs are adjusted for patient/caregiver and physician perceptions of visit MU. The base-case reflects our outpatient ALS practice. RESULTS: In the base-case, from the patient perspective, in-clinic visits cost $1,116 and video televisits cost $89 ($119 after MU-adjustment). From the institutional perspective, clinic visits cost $799, and video televisits cost $354 ($472 after MU-adjustment). Adjusted cost-savings per televisit are $997 (patient) and $327 (institution). Sensitivity analyses on 5 variables accounted for uncertainty in base-case assumptions. CONCLUSIONS: Video televisits provide marked adjusted cost-savings for patients and institutions. Adjusted costs are sensitive to perceived MU of video televisits. Future research should explore the ability of video televisits to reduce healthcare resource usage. Muscle Nerve 60: 147-154, 2019.

Developing multidisciplinary clinics for neuromuscular care and research.

Multidisciplinary care is considered the standard of care for both adult and pediatric neuromuscular disorders and has been associated with improved quality of life, resource utilization, and health outcomes. Multidisciplinary care is delivered in multidisciplinary clinics that coordinate care across multiple specialties by reducing travel burden and streamlining care. In addition, the multidisciplinary care setting facilitates the integration of clinical research, patient advocacy, and care innovation (e.g., telehealth). Yet, multidisciplinary care requires substantial commitment of staff time and resources. We calculated personnel costs in our ALS clinic in 2015 and found an average cost per patient visit of $580, of which only 45% was covered by insurance reimbursement. In this review, we will describe classic and emerging concepts in multidisciplinary care models for adult and pediatric neuromuscular disease. We will then explore the financial impact of multidisciplinary care with emphasis on sustainability and metrics to demonstrate quality and value. Muscle Nerve 56: 848-858, 2017.