Rethinking the clinical research protocol: Lessons learned from the COVID-19 pandemic and recommendations for reducing noncompliance.

BACKGROUND/AIMS: Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, 103.4 million cases and 1.1 million deaths have occurred nationally as of November 2023. Despite the benefit of mitigating measures, the pandemic's effect on participant safety is rarely documented. METHODS: This study assessed noncompliance occurring from July 2019 to August 2021 that were stratified by the date of noncompliance (before or after restrictions). Events were described by size, site, noncompliance type, primary category, subcategory, and cause. In addition, noncompliance associated with COVID-19 was analyzed to determine characteristics. RESULTS: In total, 323 noncompliance events occurred across 21,146 participants at risk in 35 protocols. The overall rate of noncompliance increased from 0.008 events per participant to 0.022 events per participant after the COVID-19 restrictions (p < 0.001). For onsite protocols, the median within protocol change in rates was 0.001 (interquartile range = 0.141) after the onset of COVID-19 restrictions (p = 0.54). For large-sized protocols (n ≥ 100), the median within protocol change in rates was also 0.001 (interquartile range = 0.017) after COVID-19 restrictions (p = 0.15). For events related to COVID-19 restrictions, 160/162 (99%) were minor deviations, 161/162 (99%) were procedural noncompliance, and 124/162 (77%) were an incomplete study visit. CONCLUSION: These noncompliance events have implications for clinical trial methodology because nonadherence to trial design can lead to participant safety concerns and loss of trial data validity. Protocols should be written to better facilitate the capture of all safety and efficacy data. This recommendation should be considered when changes occur to the protocol environment that are outside of the study team's control.

Reducing Events of Noncompliance in Neurology Human Subjects Research: the Effect of Human Subjects Research Protection Training and Site Initiation Visits.

In an effort to minimize protocol noncompliance in neurological research studies that can potentially compromise patient safety, delay completion of the study, and result in premature termination and added costs, we determined the effect of investigator trainings and site initiation visits (SIVs) on the occurrence of noncompliance events. Results of protocol audits conducted at the National Institute of Neurological Disorders and Stroke from 2003 to 2019 on 97 research protocols were retrospectively analyzed. Based on the depth of auditing and provision of investigator research training, audit data were separated into four arms: 1) Early Period, 2003 to 2012; 2) Middle Period, 2013 to 2016; and Late Period, 2017 to 2019, further divided into 3) Late Period without SIVs; and 4) Late Period with SIVs. Events of noncompliance were classified by the type of protocol deviation, the category, and the cause. In total, 952 events occurred across 1080 participants. Protocols audited during the Middle Period, compared to the Early Period, showed a decrease in the percentage of protocols with at least 1 noncompliance event. Protocols with SIVs had a further decrease in major, minor, procedural, eligibility, and policy events. Additionally, protocols audited during the Early Period had on average 0.46 major deviations per participant, compared to 0.26 events in protocols audited during the Middle Period, and 0.08 events in protocols audited during the Late Period with SIVs. Protocol deviations and noncompliance events in neurological clinical trials can be reduced by targeted investigator trainings and SIVs. These measures have major impacts on the integrity, safety, and effectiveness of human subjects research in neurology.

Research priorities in spasmodic dysphonia.

OBJECTIVE: To identify research priorities to increase understanding of the pathogenesis, diagnosis, and improved treatment of spasmodic dysphonia. STUDY DESIGN AND SETTING: A multidisciplinary working group was formed that included both scientists and clinicians from multiple disciplines (otolaryngology, neurology, speech pathology, genetics, and neuroscience) to review currently available information on spasmodic dysphonia and to identify research priorities. RESULTS: Operational definitions for spasmodic dysphonia at different levels of certainty were recommended for diagnosis and recommendations made for a multicenter multidisciplinary validation study. CONCLUSIONS: The highest priority is to characterize the disorder and identify risk factors that may contribute to its onset. Future research should compare and contrast spasmodic dysphonia with other forms of focal dystonia. Development of animal models is recommended to explore hypotheses related to pathogenesis. Improved understanding of the pathophysiology of spasmodic dysphonia should provide the basis for developing new treatment options and exploratory clinical trials. SIGNIFICANCE: This document should foster future research to improve the care of patients with this chronic debilitating voice and speech disorder by otolaryngology, neurology, and speech pathology.

Post-mortem degradation of brain glutamate decarboxylase.

The post-mortem stability of the GABA synthesizing enzyme glutamate decarboxylase (GAD) was studied by using SDS-PAGE and quantitative immunoblotting to measure the rates of degradation of GAD in the cerebral cortex, hippocampus, and cerebellum of rats and mice as a function of time after death. The intact 65- and 67-kDa isoforms of GAD (GAD(65) and GAD(67)) disappeared gradually over a 24-h period. In both rats and mice, the degraded GAD appeared as a band with an apparent molecular mass of 55-57 kDa; no significant amounts of smaller forms were observed. The 55-57 kDa band reacted with antiserum W887, which recognizes a shared epitope at the carboxyl-terminal end of both GADs, indicating that GAD was cleaved near the amino-terminal end of the molecule. GAD(67) was cleaved at a site between the amino-terminus and the epitope for antiserum W883 (located within residues 79-93 of GAD(67)), as antiserum W883 stained a 56-kDa band on the blots. The appearance of degraded GAD paralleled the loss of total GAD (GAD(65)+GAD(67)), and after 24h the 55-57 kDa band accounted for 97, 88, and 59% of the intact GAD lost from rat cerebellum, cerebral cortex and hippocampus. On a percentage basis, GAD(67) was degraded more rapidly than was GAD(65) in all brain regions studied. The loss of GAD activity was greater in rat than mouse brain, even though the percent loss of intact GAD protein was similar.