A comparison of machine learning methods to find clinical trials for inclusion in new systematic reviews from their PROSPERO registrations prior to searching and screening.

Searching for trials is a key task in systematic reviews and a focus of automation. Previous approaches required knowing examples of relevant trials in advance, and most methods are focused on published trial articles. To complement existing tools, we compared methods for finding relevant trial registrations given a International Prospective Register of Systematic Reviews (PROSPERO) entry and where no relevant trials have been screened for inclusion in advance. We compared SciBERT-based (extension of Bidirectional Encoder Representations from Transformers) PICO extraction, MetaMap, and term-based representations using an imperfect dataset mined from 3632 PROSPERO entries connected to a subset of 65,662 trial registrations and 65,834 trial articles known to be included in systematic reviews. Performance was measured by the median rank and recall by rank of trials that were eventually included in the published systematic reviews. When ranking trial registrations relative to PROSPERO entries, 296 trial registrations needed to be screened to identify half of the relevant trials, and the best performing approach used a basic term-based representation. When ranking trial articles relative to PROSPERO entries, 162 trial articles needed to be screened to identify half of the relevant trials, and the best-performing approach used a term-based representation. The results show that MetaMap and term-based representations outperformed approaches that included PICO extraction for this use case. The results suggest that when starting with a PROSPERO entry and where no trials have been screened for inclusion, automated methods can reduce workload, but additional processes are still needed to efficiently identify trial registrations or trial articles that meet the inclusion criteria of a systematic review.

Reporting and Representation of Participant Race and Ethnicity in National Institutes of Health-Funded Pediatric Clinical Trials.

Importance: Enrolling racially and ethnically diverse pediatric research participants is critical to ensuring equitable access to health advances and generalizability of research findings. Objectives: To examine the reporting of race and ethnicity for National Institutes of Health (NIH)-funded pediatric clinical trials and to assess the representation of pediatric participants from different racial and ethnic groups compared with distributions in the US population. Design, Setting, and Participants: This cross-sectional study included NIH-funded pediatric (ages 0-17 years) trials with grant funding completed between January 1, 2017, and December 31, 2019, and trial results reported as of June 30, 2022. Exposures: National Institutes of Health policies and guidance statements on the reporting of race and ethnicity of participants in NIH-funded clinical trials. Main Outcomes and Measures: The main outcome was reporting of participant race and ethnicity for NIH-funded pediatric clinical trials in publications and ClinicalTrials.gov. Results: There were 363 NIH-funded pediatric trials included in the analysis. Reporting of race and ethnicity data was similar in publications and ClinicalTrials.gov, with 90.3% (167 of 185) of publications and 93.9% (77 of 82) of ClinicalTrial.gov reports providing data on race and/or ethnicity. Among the 160 publications reporting race, there were 43 different race classifications, with only 3 publications (1.9%) using the NIH-required categories. By contrast, in ClinicalTrials.gov, 61 reports (79.2%) provided participant race and ethnicity using the NIH-specified categories (P < .001). There was racially and ethnically diverse enrollment of pediatric participants, with overrepresentation of racial and ethnic minority groups compared with the US population. Conclusions and Relevance: This cross-sectional study of NIH-funded pediatric clinical trials found high rates of reporting of participant race and ethnicity, with diverse representation of trial participants. These findings suggest that the NIH is meeting its directive of ensuring diverse participant enrollment in the research it supports.

Characteristics and Results of Pediatric Medical Device Studies: 2017-2022.

OBJECTIVES: The development of medical devices for children faces unique challenges that have contributed to a paucity of devices specifically designed and tested for children. Increased knowledge on research activities for pediatric devices can guide optimal study design and ensure timely dissemination of clinical findings. METHODS: We performed a cross-sectional analysis of interventional studies registered on ClinicalTrials.gov, initiated January 1, 2017, through December 12, 2022, evaluating a Food and Drug Administration-regulated class II or III device, and enrolling any pediatric patients (aged ≤17 years). Data were extracted from ClinicalTrials.gov on study characteristics and from Devices@FDA on device features. For completed studies, we determined whether results were reported in a peer-reviewed publication as of December 27, 2022. RESULTS: Among 482 studies, 406 (84.2%) examined a class II device and 76 (15.8%) a class III device. The most common device types were diabetes-related devices (N = 57, 11.8%) and monitors and measurement devices (N = 39, 8.1%). Most studies were single-center (N = 326, 67.6%), used a nonrandomized (N = 255, 52.9%), open label (N = 350, 72.6%) design, and were funded by academic institutions (N = 278, 57.7%) or industry (N = 142, 29.5%). A total of 291 (60.4%) studies included a primary outcome of only efficacy without safety endpoints. Among completed studies, more than half (N = 64, 51.6%) enrolled <50 participants and 71.0% (N = 88) <100. After median follow-up of 3.0 years, results were available in publications for 27 (21.8%) completed studies. CONCLUSIONS: Our findings serve to inform programs and initiatives seeking to increase pediatric-specific device development. In addition to considerations on ensuring rigorous trial design, greater focus is needed on timely dissemination of results generated in pediatric device studies.

Data Sharing for Pediatric Clinical Trials Funded by the US National Institutes of Health.

This cross-sectional study assesses declared data sharing in publications for a recent set of pediatric clinical trials funded by the US National Institutes of Health (NIH).

Clinical development of new drugs for adults and children with cancer, 2010-2020.

BACKGROUND: Many new molecular entities enter clinical development to evaluate potential therapeutic benefits for oncology patients. We characterized adult and pediatric development of the set of new molecular entities that started clinical testing in 2010-2015 worldwide. METHODS: We extracted data from AdisInsight, an extensive database of global pharmaceutical development, and the FDA.gov website. We followed the cohort of new molecular entities initiating first-in-human phase I clinical trials in 2010-2015 to the end of 2020. For each new molecular entity, we determined whether it was granted US Food and Drug Administration (FDA) approval, studied in a trial open to pediatric enrollment, or stalled during development. We characterized the cumulative incidence of these endpoints using statistical methods for censored data. RESULTS: The 572 new molecular entities starting first-in-human studies in 2010-2015 were studied in 6142 trials by the end of 2020. Most new molecular entities were small molecules (n = 316, 55.2%), antibodies (n = 148, 25.9%), or antibody-drug conjugates (n = 44, 7.7%). After a mean follow-up of 8.0 years, 173 new molecular entities did not advance beyond first-in-human trials, and 39 were approved by the FDA. New molecular entities had a 10.4% estimated probability (95% confidence interval = 6.6% to 14.1%) of being approved by the FDA within 10 years of first-in-human trials. After a median of 4.6 years since start of first-in-human trials, 67 (11.7%) new molecular entities were tested in trials open to pediatric patients, and 5 (0.9%) were approved for pediatric indications. CONCLUSIONS: More efficient clinical development strategies are needed to evaluate new cancer therapies, especially for children, and incorporate approaches to ensure knowledge gain from investigational products that stall in development.

Dissemination of the Results of Pediatric Clinical Trials Funded by the US National Institutes of Health.

This study examines practices related to trial registration and results submission in ClinicalTrials.gov and publication of pediatric clinical trials funded by the National Institutes of Health.

Sensory neuron-expressed TRPC3 mediates acute and chronic itch.

ABSTRACT: Chronic pruritus is a prominent symptom of allergic contact dermatitis (ACD) and represents a huge unmet health problem. However, its underlying cellular and molecular mechanisms remain largely unexplored. TRPC3 is highly expressed in primary sensory neurons and has been implicated in peripheral sensitization induced by proinflammatory mediators. Yet, the role of TRPC3 in acute and chronic itch is still not well defined. Here, we show that, among mouse trigeminal ganglion (TG) neurons, Trpc3 mRNA is predominantly expressed in nonpeptidergic small diameter TG neurons of mice. Moreover, Trpc3 mRNA signal was present in most presumptively itch sensing neurons. TRPC3 agonism induced TG neuronal activation and acute nonhistaminergic itch-like and pain-like behaviors in naive mice. In addition, genetic deletion of Trpc3 attenuated acute itch evoked by certain common nonhistaminergic pruritogens, including endothelin-1 and SLIGRL-NH2. In a murine model of contact hypersensitivity (CHS), the Trpc3 mRNA expression level and function were upregulated in the TG after CHS. Pharmacological inhibition and global knockout of Trpc3 significantly alleviated spontaneous scratching behaviors without affecting concurrent cutaneous inflammation in the CHS model. Furthermore, conditional deletion of Trpc3 in primary sensory neurons but not in keratinocytes produced similar antipruritic effects in this model. These findings suggest that TRPC3 expressed in primary sensory neurons may contribute to acute and chronic itch through a histamine independent mechanism and that targeting neuronal TRPC3 might benefit the treatment of chronic itch associated with ACD and other inflammatory skin disorders.

High-risk Therapeutic Devices Approved by the US Food and Drug Administration for Use in Children and Adolescents From 2016 to 2021.

This cohort study examines the characteristics of high-risk therapeutic devices approved by the US Food and Drug Administration for use in children and adolescents between 2016 and 2021.

Who Makes the Choice: Ethical Considerations Regarding Instituting Breastfeeding in a Mother Who Has Compromised Mental Capacity.

This case reports an ethical dilemma in which a mother who had recently delivered a baby through cesarean section after sustaining life-threatening injuries in a car accident did not have documented wishes whether she wanted to breastfeed. Her medical condition rendered her temporarily mentally incapacitated and critically ill, and the lactation medicine team was consulted about whether lactation choice should be preserved by pumping. Complicating considerations in this case were (1) lack of family or designated decision-makers available at the time of injury and emergent delivery, (2) lack of prenatal care, and (3) complex social situation, including prior history of illicit substance use, and state removal of other children into foster care. This case raises important ethical considerations regarding breastfeeding decision-making when a mother is incapable of making the decision, and if there is an intrinsic right for an infant to be breastfed in situations where maternal choice to lactate or to formula feed is unknown. Ultimately, the mother chose to discontinue breastfeeding once she was able to voice her own opinion. The issues discussed in this study may be relevant for future cases when providing guidance on the ethical argument to preserve maternal choice when a mother is critically ill and mentally incapacitated.