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.
Abstract 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.
Abstract 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.
This study uses data from US Food and Drug Administration (FDA) databases to quantify approval of high-risk cardiovascular devices for use in pediatric populations and assess the clinical evidence supporting the approvals.
1563 Background: Many investigational drugs start clinical testing to evaluate potential therapeutic benefits for oncology patients, but few eventually receive FDA approval. Moreover, only a small number is evaluated in pediatric populations, potentially contributing to the paucity of new approved drugs for young patients with cancer. Limited information is available on the development pipeline of investigational drugs, including the range of drug types entering clinical trials, trial phases at which development stalls, or rate of regulatory approval. To inform current clinical development efforts, we characterized the development and outcomes for a comprehensive sample of New Molecular Entities (NMEs) that started clinical testing worldwide in 2010-2015. Methods: We performed a longitudinal study using AdisInsight, a commercial database of global pharmaceutical research and development. This is a comprehensive database of drug development activity, which collects and curates data from trial registries, conference proceedings, journal publications, and press releases. Using these data, we identified all NMEs starting their first clinical trial for an oncology indication in 2010-2015. We followed each NME from the start of its first phase I trial to the end of 2020, and identified all associated trials, final development status, and FDA deliberations. We classified trials as pediatric-eligible if patients aged < 18 years were eligible for participation. We used the Drugs@FDA website to identify all FDA actions, including marketing approvals and requests for pediatric trials under pediatric programs (i.e. BPCA requests or PREA requirements). Results: A total of 572 NMEs started initial phase I clinical trials in 2010-2015. Among these, the most studied classes were small molecules (N, %: 316, 55%), antibodies (148, 26%), and antibody-drug conjugates (44, 8%). Overall, the NMEs were studied in 6,141 clinical trials by the end of 2020, with a median of 3 trials per NME. The highest pre-approval development phase reached by an NME was phase I for 325 (57%), phase II for 153 (27%), and phase III for 94 (16%). Only 39 NMEs (7%) were approved by the FDA by the end of 2020. Among approved NMEs, the median time (range) from start of first phase I trial to date of first approval was 6 (3-10) years. Among all NMEs, only 67 (12%) were tested in pediatric-eligible trials by the end of 2020, and 5 (< 1%) were approved for use in selected pediatric populations. Three of these had been subject to BPCA requests, and all had PREA requirements waived. Conclusions: More efficient clinical development strategies are needed to accelerate the production of new cancer therapies, especially for children. Analyses such as this one should be conducted regularly to help identify areas in need of innovation and to assess the potential impact of regulatory initiatives (e.g. the RACE act, effective since August 2020).
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.
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.
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).
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.
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