Reporting of clinical trial safety results in ClinicalTrials.gov for FDA-approved drugs: A cross-sectional analysis.

BACKGROUND: Adverse events identified during clinical trials can be important early indicators of drug safety, but complete and timely data on safety results have historically been difficult to access. The aim was to compare the availability, completeness, and concordance of safety results reported in ClinicalTrials.gov and peer-reviewed publications. METHODS: We analyzed clinical trials used in the Food and Drug Administration safety assessment of new drugs approved between 1 July 2018 and 30 June 2019. The key safety outcomes examined were all-cause mortality, serious adverse events, adverse events, and withdrawals due to adverse events. Availability of safety results was measured by the presence and timing of a record of trial-level results in ClinicalTrials.gov and a corresponding peer-reviewed publication. For the subset of trials with available results, completeness was defined as the reporting of safety results for all participants and compared between ClinicalTrials.gov and publications. To assess concordance, we compared the numeric results for safety outcomes reported in ClinicalTrials.gov and publications to results in Food and Drug Administration trial reports. RESULTS: Among 156 trials studying 52 drugs, 91 (58.3%) trials reported safety results in ClinicalTrials.gov and 106 (67.9%) in peer-reviewed publications (risk difference = -9.6%, 95% confidence interval = -20.3 to 1.0). All-cause mortality was reported sooner in published articles compared with ClinicalTrials.gov (log-rank test, p = 0.01). There was no difference in time to reporting for serious adverse events (p = 0.05), adverse events (p = 0.09), or withdrawals due to adverse events (p = 0.20). Complete reporting of all-cause mortality was similar in ClinicalTrials.gov and publications (74.7% vs 78.3%, respectively; risk difference = -3.6%, 95% confidence interval = -15.5 to 8.3) and higher in ClinicalTrials.gov for serious adverse events (100% vs 79.2%; risk difference = 20.8%, 95% confidence interval = 13.0 to 28.5) and adverse events (100% vs 86.8%; risk difference = 13.2%, 95% confidence interval = 6.8 to 19.7). Withdrawals due to adverse events were less often completely reported in ClinicalTrials.gov (62.6% vs 92.5%; risk difference = -29.8%, 95% confidence interval = -40.1 to -18.7). No difference was found in concordance of results between ClinicalTrials.gov and publications for all-cause mortality, serious adverse events, or withdrawals due to adverse events. CONCLUSION: Safety results were available in ClinicalTrials.gov at a similar rate as in peer-reviewed publications, with more complete reporting of certain safety outcomes in ClinicalTrials.gov. Future efforts should consider adverse event reporting in ClinicalTrials.gov as an accessible data source for post-marketing surveillance and other evidence synthesis tasks.

Impact of a Collective Intelligence Tailored Messaging System on Smoking Cessation: The Perspect Randomized Experiment.

BACKGROUND: Outside health care, content tailoring is driven algorithmically using machine learning compared to the rule-based approach used in current implementations of computer-tailored health communication (CTHC) systems. A special class of machine learning systems ("recommender systems") are used to select messages by combining the collective intelligence of their users (ie, the observed and inferred preferences of users as they interact with the system) and their user profiles. However, this approach has not been adequately tested for CTHC. OBJECTIVE: Our aim was to compare, in a randomized experiment, a standard, evidence-based, rule-based CTHC (standard CTHC) to a novel machine learning CTHC: Patient Experience Recommender System for Persuasive Communication Tailoring (PERSPeCT). We hypothesized that PERSPeCT will select messages of higher influence than our standard CTHC system. This standard CTHC was proven effective in motivating smoking cessation in a prior randomized trial of 900 smokers (OR 1.70, 95% CI 1.03-2.81). METHODS: PERSPeCT is an innovative hybrid machine learning recommender system that selects and sends motivational messages using algorithms that learn from message ratings from 846 previous participants (explicit feedback), and the prior explicit ratings of each individual participant. Current smokers (N=120) aged 18 years or older, English speaking, with Internet access were eligible to participate. These smokers were randomized to receive either PERSPeCT (intervention, n=74) or standard CTHC tailored messages (n=46). The study was conducted between October 2014 and January 2015. By randomization, we compared daily message ratings (mean of smoker ratings each day). At 30 days, we assessed the intervention's perceived influence, 30-day cessation, and changes in readiness to quit from baseline. RESULTS: The proportion of days when smokers agreed/strongly agreed (daily rating ≥4) that the messages influenced them to quit was significantly higher for PERSPeCT (73%, 23/30) than standard CTHC (44%, 14/30, P=.02). Among less educated smokers (n=49), this difference was even more pronounced for days strongly agree (intervention: 77%, 23/30; comparison: 23%, 7/30, P<.001). There was no significant difference in the frequency which PERSPeCT randomized smokers agreed or strongly agreed that the intervention influenced them to quit smoking (P=.07) and use nicotine replacement therapy (P=.09). Among those who completed follow-up, 36% (20/55) of PERSPeCT smokers and 32% (11/34) of the standard CTHC group stopped smoking for one day or longer (P=.70). CONCLUSIONS: Compared to standard CTHC with proven effectiveness, PERSPeCT outperformed in terms of influence ratings and resulted in similar cessation rates. CLINICALTRIAL: Clinicaltrials.gov NCT02200432; https://clinicaltrials.gov/ct2/show/NCT02200432 (Archived by WebCite at http://www.webcitation.org/6lEJY1KEd).

Age-Dependent Differences in Blood Levels of Glial Fibrillary Acidic Protein but Not Ubiquitin Carboxy-Terminal Hydrolase L1 in Children.

OBJECTIVES: Despite the growing evidence of the clinical utility of blood-brain biomarkers in adults with traumatic brain injury (TBI), less is known about the performance of these biomarkers in children. We characterize age-dependent differences in levels of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) in children without TBI. METHODS: Plasma biobank specimens from children and adolescents aged 0-<19 years without TBI were obtained, and UCH-L1 and GFAP levels were quantified. The relationship between age and biomarker expression was determined using previously defined aged epochs (<3.5 years, 3.5 years to <11 years, 11 years and older), then biomarker levels were compared with established thresholds for ruling out the need for a head CT in adults with a mild TBI (mTBI) (UCH-L1 400 pg/mL, GFAP 35 pg/mL). RESULTS: The age range of the 366 control patients was 3 months-18 years. There was a significant negative association between age and GFAP but not UCH-L1. Only 1.4% of samples exceeded the UCH-L1 cutoff; however, 20% of samples exceeded the GFAP cutoff and 100% children younger than 3.5 years had values that exceeded the cutoff. DISCUSSION: Age seems to modify physiologic plasma GFAP levels. Diagnostic cutoffs for TBI based on GFAP but not UCH-L1 and may need to be adjusted in children younger than 11 years.

Development of the Precision Link Biobank at Boston Children's Hospital: Challenges and Opportunities.

Increasingly, biobanks are being developed to support organized collections of biological specimens and associated clinical information on broadly consented, diverse patient populations. We describe the implementation of a pediatric biobank, comprised of a fully-informed patient cohort linking specimens to phenotypic data derived from electronic health records (EHR). The Biobank was launched after multiple stakeholders' input and implemented initially in a pilot phase before hospital-wide expansion in 2016. In-person informed consent is obtained from all participants enrolling in the Biobank and provides permission to: (1) access EHR data for research; (2) collect and use residual specimens produced as by-products of routine care; and (3) share de-identified data and specimens outside of the institution. Participants are recruited throughout the hospital, across diverse clinical settings. We have enrolled 4900 patients to date, and 41% of these have an associated blood sample for DNA processing. Current efforts are focused on aligning the Biobank with other ongoing research efforts at our institution and extending our electronic consenting system to support remote enrollment. A number of pediatric-specific challenges and opportunities is reviewed, including the need to re-consent patients when they reach 18 years of age, the ability to enroll family members accompanying patients and alignment with disease-specific research efforts at our institution and other pediatric centers to increase cohort sizes, particularly for rare diseases.