INDUCE-2: A Phase I/II, open-label, two-part study of feladilimab in combination with tremelimumab in patients with advanced solid tumors.

Combining immunotherapies with distinct mechanisms of action has the potential to overcome treatment resistance and improve outcomes. The inducible T-cell co-stimulator (ICOS) agonist feladilimab is directed at enhancing T-cell activation and function, thereby promoting an antitumor response. INDUCE-2 (NCT03693612) was a Phase I/II, open-label, two-part study evaluating the anti-ICOS agonist feladilimab in combination with the anti-CTLA-4 antibody tremelimumab in patients with select advanced solid tumors. Objectives of Part 1 were to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of feladilimab in combination with tremelimumab. In Part 2, the antitumor activity of the combination (administered at the RP2D determined in Part 1) was to be assessed in patients with relapsed/refractory head and neck squamous cell carcinoma. Primary endpoints included the rates of dose-limiting toxicities (DLTs), adverse events (AEs), AEs of special interest, and serious AEs. Secondary endpoints included overall response rate, while biomarker assessment was exploratory. A total of 26 patients were enrolled, 18 (69%) of whom had completed the study at end date. One patient, in the highest dose group (24/225 mg feladilimab/tremelimumab), experienced a DLT 18 days after the first dose of study treatment. All patients experienced at least one AE; AEs led to treatment discontinuation in four (15%) patients. Partial response was observed in one patient. Feladilimab in combination with tremelimumab was well-tolerated but showed limited efficacy. Based on the totality of data from Part 1, it was decided not to continue with Part 2.

Designing a Visit Schedule for Longitudinal Studies in Pediatric Research.

A challenge for longitudinal studies is combining individual assessments into visits that are scientifically logical, not burdensome for participants, well-choreographed, and operationally feasible. The visits then need to be sequenced and spaced to address the scientific goals and generate a data archive that is sufficiently robust and well-documented to support subsequent analyses. This paper summarizes comprehensive multi-disciplinary activities that were coordinated to design the content, format, and structure of the National Children's Study and concurrently serve as a model and resource for other studies.

Principles of Researching Health Disparities in Longitudinal Cohort Studies Enrolling Children.

Health disparities are defined on the basis of specific populations that, when compared to the general population, have a significant disparity on the rate of disease incidence, prevalence, morbidity, mortality, or survival. People that experience health disparities can be defined by multiple criteria. As the diversity of the United States broadens and increases, research on the origins and causes of health disparities becomes more important to support a healthy general population. Children are particularly sensitive to and vulnerable to health disparities due to the potentially life long consequences of events during periods of critical organ, intellectual and social development. The concept of health justice whereby each individual has the opportunity to realize their full health potential can only be realized with proper understanding and relevant data to frame practice, policy and actions. The National Children's Study (NCS) was a longitudinal birth cohort study designed to incorporate the principles of the Federal Collaboration on Health Disparities Research in consultation with subject matter experts, community representatives, and ongoing evaluation to ensure high quality and relevant data on factors that impact health outcomes. The NCS developed and tested a model of enrolling a diverse population, capturing and integrating data using a life course framework, constructing individual profiles, then aggregating individuals into groups based on profiles and outcomes. This approach is applicable to other longitudinal cohort studies.

NCS Assessments of the Motor, Sensory, and Physical Health Domains.

As part of the National Children's Study (NCS) comprehensive and longitudinal assessment of the health status of the whole child, scientific teams were convened to recommend assessment measures for the NCS. This manuscript documents the work of three scientific teams who focused on the motor, sensory, or the physical health aspects of this assessment. Each domain team offered a value proposition for the importance of their domain to the health outcomes of the developing infant and child. Constructs within each domain were identified and measures of these constructs proposed. Where available extant assessments were identified. Those constructs that were in need of revised or new assessment instruments were identified and described. Recommendations also were made for the age when the assessments should take place.

Health Measurement Model-Bringing a Life Course Perspective to Health Measurement: The PRISM Model.

Health is a multidimensional concept that is challenging to measure, and in the rapidly evolving developmental changes that occur during the first 21 years of human life, requires a dynamic approach to accurately capture the transitions, and overall arc of a complex process of internal and external interactions. We propose an approach that integrates a lifecourse framework with a layered series of assessments, each layer using a many to many mapping, to converge on four fundamental dimensions of health measurement-Potential, Adaptability, Performance, and Experience. The four dimensions can conceptually be mapped onto a plane with each edge of the resulting quadrilateral corresponding to one dimension and each dimensions assessment calibrated against a theoretical ideal. As the plane evolves over time, the sequential measurements will form a volume. We term such a model the Prism Model, and describe conceptually how single domain assessments can be built up to generate the holistic description through the vehicle of a layer of Exemplar Cases. The model is theoretical but future work can use the framework and principles to generate scalable and adaptable applications that can unify and improve the precision of serial measurements that integrate environmental and physiologic influences to improve the science of child health measurement.

Challenges in clinical trials for children and young people.

There is a well-known knowledge gap regarding the efficacy and safety of medicines in children of all ages and children are often treated with medicines off-label. Children are thus deprived of treatment based on the same quality of information that guides treatment in adults. The knowledge gap regarding efficacy and safety of medicines in children has been acknowledged by authorities and is reflected in legislation both in North America and in the European Union. Recent reports on the effects of legislation indicates that paediatric clinical trials remain a challenge.Paediatric clinical trials are needed in the entire developmental age spectrum and are especially needed in certain therapy areas. Paediatric clinical trials have special features compared with trials in adults, and these need to be taken into account. These special features include scientific issues related to small samples and heterogeneity, the consent/assent procedure, the need for age-appropriate study information, specific outcomes and safety issues related to development and maturation. Competence in paediatric clinical trials is required in both designing, planning, co-ordinating and organising paediatric clinical trials, as well as research infrastructure and networks to increase power and disseminate information and expert advice. Strengthening of paediatric clinical research is essential to facilitate generating the data that will let children enjoy new medical advances in a similar manner as adults.

Prerequisites to support high-quality clinical trials in children and young people.

Children have the right to treatment based on the same quality of information that guides treatment in adults. Without the proper evaluation of medicinal products and devices in paediatric clinical trials that are designed to meet the rigorous standards of the competent authorities, children are discriminated from advances in medicine. There are regulatory, scientific and ethical incentives to address the knowledge gap regarding efficacy and safety of medicines in the paediatric population. High-quality clinical trials involving children of all ages can generate data that will ultimately close the knowledge gaps and support decision making.For clinical trials that enrol children, the needs are specialised and often resource intensive. Prerequisites for successful paediatric clinical trials are personnel with training in both paediatrics and neonatology and expertise in clinical trials in these populations. Moreover, national and international networks for efficient collaboration, dissemination of information, and sharing of resources and expertise are also needed, together with competent, efficient and high-quality local infrastructure with effective processes. Monitoring and oversight bodies with the relevant competence, including expertise in paediatrics, is also an important prerequisite for paediatric clinical trials. Compromise in any of these components will compromise the downstream results.This paper discusses the structures and competences needed in order to perform effective, high-quality paediatric clinical trials with the ultimate goal of better medicines and treatments for children. We propose a model of examining the process as a series of components that each has to be optimised, then all the components are actively optimised to function together as an ecosystem, and the resulting ecosystem functions well with the general research system and the healthcare delivery system.

What Could the Future of Safety Monitoring Look Like?

Like much of the clinical research and health care provider enterprise, the data capture and archiving for harm, probability of harm, and impact of intervention-related events is fragmented, inconsistent, and lacks standards to perform the types of operations that could inform researchers, practitioners, and patients in a timely way of actions and policies. The entire system of assessments, terminology, data formats and structure, analyses, and dissemination would benefit from changes based on adherence to a process framework of detect, describe, analyze, and react in the context of recognizing the multiple pathways and factors that lead to any specific outcome or series of outcomes. Existing tools, if properly applied, can form the basis for the next generation of data systems, processes, analyses, and sharing to address most of the current challenges.

Weight estimation among multi-racial/ethnic infants and children aged 0-5·9 years in the USA: simple tools for a critical measure.

OBJECTIVE: In resource-constrained facilities or during resuscitation, immediate paediatric weight estimation remains a fundamental challenge. We aimed to develop and validate weight estimation models based on ulna length and forearm width and circumference measured by simple and portable tools; and to compare them against previous methods (advanced paediatric life support (APLS), Theron and Traub-Johnson formulas). DESIGN: Cross-sectional analysis of anthropometric measurements. Four ulna- and forearm-based weight estimation models were developed in the training set (n 1016). Assessment of bias, precision and accuracy was examined in the validation set (n 457). SETTING: National Children's Study-Formative Research in Anthropometry (2011-2012). SUBJECTS: Multi-racial/ethnic infants and children aged <6 years (n 1473). RESULTS: Developed Models 1-4 had high predictive precision (R 2=0·91-0·97). Mean percentage errors between predicted and measured weight were significantly smaller across the developed models (0·1-0·7 %) v. the APLS, Theron and Traub-Johnson formulas (-1·7, 9·2 and -4·9 %, respectively). Root-mean-squared percentage error was overall smaller among Models 1-4 v. the three existing methods (range=7·5-8·7 v. 9·8-13·3 %). Further, Models 1-4 were within 10 and 20 % of actual weight in 72-87 and 95-99 % of the weight estimations, respectively, which outperformed any of the three existing methods. CONCLUSIONS: Ulna length, forearm width and forearm circumference by simple and portable tools could serve as valid and reliable surrogate measures of weight among infants and children aged <6 years with improved precision over the existing age- or length-based methods. Further validation of these models in physically impaired or non-ambulatory children is warranted.

Assessment of a shortened informed consent form for pediatric research: a pilot study.

BACKGROUND: Inherent to clinical research is the informed consent process, with the informed consent form (ICF), a key component of human participant protections. We wished to examine whether a shortened and simplified ICF, accompanied by an appendix, improved participant understanding of a study compared with a conventional ICF. METHODS: A shortened ICF was developed from an existing conventional ICF for a neonatal study. Either the shortened or conventional ICF was randomly distributed to members of two parental advocacy groups. Participants answered survey questions about the form they received. RESULTS: Thirty-one out of forty-one (76%) parents in the shortened ICF and 28/41 (68%) in the conventional ICF group responded. Significantly more parents in the shortened ICF group found their form "short and to the point". Although they also stated that the shortened ICF did not provide enough information, there were no significant differences between groups measuring the understanding of key study components. CONCLUSION: A shortened ICF did not impact the understanding of the clinical trial. It will be important to compare the shortened and conventional forms in actual clinical trials.

Frameworks for Evaluating Medicines in Children.

PURPOSE: To summarise contemporary approaches to evaluating medicines in children, emphasizing topics that are often misunderstood by one or more stakeholder groups. METHODS: A narrative review that integrates the literature with experience in multiple settings. FINDINGS: Children and young people need specific approaches to research about drugs because of growth and development. Specific approaches include practicalities such as the volume, frequency and technique of blood samples, and recruitment, including consent by proxy decision-makers and assent by children/young people. The design of drug development programmes includes working with children/young people from an early stage and minimising the burden of research through careful design while optimizing the contribution of extant, high quality information (including extrapolation).Regulators, academics, the pharmaceutical industry and other communities are well-placed to support pediatric drug development. Regulatory challenges include legislation that drives the extension to children of medicines used in adults (rather than a focus on the needs of children) and diversity between jurisdictions. Academics can improve the impact of their work by ensuring that data can be used in drug development programmes after they have answered a well-defined study question. Pharmaceutical companies, and public research funders can promote good return on the investment made in research (including the investment made by children/young people) by supporting data management to allow data reuse. IMPLICATIONS: a greater understanding of pediatric issues is relevant to diverse research communities that work to advance pharmacotherapy.

Immunization in pregnancy clinical research in low- and middle-income countries - Study design, regulatory and safety considerations.

Immunization of pregnant women is a promising public health strategy to reduce morbidity and mortality among both the mothers and their infants. Establishing safety and efficacy of vaccines generally uses a hybrid design between a conventional interventional study and an observational study that requires enrolling thousands of study participants to detect an unknown number of uncommon events. Historically, enrollment of pregnant women in clinical research studies encountered many barriers based on risk aversion, lack of knowledge, and regulatory ambiguity. Conducting research enrolling pregnant women in low- and middle-income countries can have additional factors to address such as limited availability of baseline epidemiologic data on disease burden and maternal and neonatal outcomes during and after pregnancy; challenges in recruiting and retaining pregnant women in research studies, variability in applying and interpreting assessment methods, and variability in locally acceptable and available infrastructure. Some measures to address these challenges include adjustment of study design, tailoring recruitment, consent process, retention strategies, operational and logistical processes, and the use of definitions and data collection methods that will align with efforts globally.

Introduction and Goals for the National Children's Study.

The National Children's Study (NCS) evolved in concept and planning to become an integrated systems based initiative to assess a full spectrum of health and capture the environmental factors and other influences that shape the trajectory of child development. The NCS built on prior work in health assessment, epidemiology, logistics, and methodology in order to address the broad goals of its mandate. To develop the specific methods and tools to conduct a study in multiple environments outside conventional health care delivery clinics the NCS invested in new approaches such as informatics, study operations, and the establishment of a Health Measurements Network to provide accurate, cost effective, and scientifically valid data that would be interoperable with data collected by other longitudinal studies around the world as well as with major national and international health improvement initiatives.

Development of a Pediatric Adverse Events Terminology.

In 2009, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Pediatric Terminology Harmonization Initiative to establish a core library of terms to facilitate the acquisition and sharing of knowledge between pediatric clinical research, practice, and safety reporting. A coalition of partners established a Pediatric Terminology Adverse Event Working Group in 2013 to develop a specific terminology relevant to international pediatric adverse event (AE) reporting. Pediatric specialists with backgrounds in clinical care, research, safety reporting, or informatics, supported by biomedical terminology experts from the National Cancer Institute's Enterprise Vocabulary Services participated. The multinational group developed a working definition of AEs and reviewed concepts (terms, synonyms, and definitions) from 16 pediatric clinical domains. The resulting AE terminology contains >1000 pediatric diseases, disorders, or clinical findings. The terms were tested for proof of concept use in 2 different settings: hospital readmissions and the NICU. The advantages of the AE terminology include ease of adoption due to integration with well-established and internationally accepted biomedical terminologies, a uniquely temporal focus on pediatric health and disease from conception through adolescence, and terms that could be used in both well- and underresourced environments. The AE terminology is available for use without restriction through the National Cancer Institute's Enterprise Vocabulary Services and is fully compatible with, and represented in, the Medical Dictionary for Regulatory Activities. The terminology is intended to mature with use, user feedback, and optimization.

Global alignment of immunization safety assessment in pregnancy - The GAIA project.

Immunization in pregnancy provides a promising contribution to globally reducing neonatal and under-five childhood mortality and morbidity. Thorough assessment of benefits and risks for the primarily healthy pregnant women and their unborn babies is required. The GAIA project was formed in response to the call of the World Health Organization for a globally concerted approach to actively monitor the safety of vaccines and immunization in pregnancy programs. GAIA aims to improve the quality of outcome data from clinical vaccine trials in pregnant women with a specific focus on the needs and requirements for safety monitoring in LMIC. In the first year of the project, a large and functional network of experts was created. The first outputs include a guidance document for clinical trials of immunization in pregnancy, a basic data collection guide, ten case definitions of key obstetric and neonatal health outcomes, an ontology of key terms and a map of pertinent disease codes. The GAIA Network is designed as an open and growing forum for professionals sharing the GAIA vision and aim. Based on the initial achievements, tools and services are developed to support investigators and strengthen immunization in pregnancy programs with specific focus on LMIC.

Guideline for collection, analysis and presentation of safety data in clinical trials of vaccines in pregnant women.

Vaccination during pregnancy is increasingly being used as an effective approach for protecting both young infants and their mothers from serious infections. Drawing conclusions from published studies in this area can be difficult because of the inability to compare vaccine trial results across different studies and settings due to the heterogeneity in the definitions of terms used to assess the safety of vaccines in pregnancy and the data collected in such studies. The guidelines proposed in this document have been developed to harmonize safety data collection in all phases of clinical trials of vaccines in pregnant women and apply to data from the mother, fetus and infant. Guidelines on the prioritization of the data to be collected is also provided to allow applicability in various geographic, cultural and resource settings, including high, middle and low-income countries.

Improving the value of clinical research through the use of Common Data Elements.

The use of Common Data Elements can facilitate cross-study comparisons, data aggregation, and meta-analyses; simplify training and operations; improve overall efficiency; promote interoperability between different systems; and improve the quality of data collection. A Common Data Element is a combination of a precisely defined question (variable) paired with a specified set of responses to the question that is common to multiple datasets or used across different studies. Common Data Elements, especially when they conform to accepted standards, are identified by research communities from variable sets currently in use or are newly developed to address a designated data need. There are no formal international specifications governing the construction or use of Common Data Elements. Consequently, Common Data Elements tend to be made available by research communities on an empiric basis. Some limitations of Common Data Elements are that there may still be differences across studies in the interpretation and implementation of the Common Data Elements, variable validity in different populations, and inhibition by some existing research practices and the use of legacy data systems. Current National Institutes of Health efforts to support Common Data Element use are linked to the strengthening of National Institutes of Health Data Sharing policies and the investments in data repositories. Initiatives include cross-domain and domain-specific resources, construction of a Common Data Element Portal, and establishment of trans-National Institutes of Health working groups to address technical and implementation topics. The National Institutes of Health is seeking to lower the barriers to Common Data Element use through greater awareness and encourage the culture change necessary for their uptake and use. As National Institutes of Health, other agencies, professional societies, patient registries, and advocacy groups continue efforts to develop and promote the responsible use of Common Data Elements, particularly if linked to accepted data standards and terminologies, continued engagement with and feedback from the research community will remain important.

Predictive Models for Characterizing Disparities in Exclusive Breastfeeding Performance in a Multi-ethnic Population in the US.

OBJECTIVES: Maternal lactation performance varies across populations, yet the relative impact of maternal sociodemographics, perinatal factors, and birth outcomes on disparities in exclusive breastfeeding (XBR) outcomes is not well known. We aimed to develop predictive models and compare the relative contribution of predictors for XBR initiation and XBR ≥ 6 months. METHODS: Infant feeding data were obtained from women with children aged 0-6 years (n = 1471) in a multi-ethnic cross-sectional study in the US (2011-2012). We compared discriminant ability of predictors for ever XBR and XBR ≥ 6 months using discriminant function analysis, respectively. We also calculated adjusted ORs for factors associated with XBR outcomes and breast-bottle feeding (BrBot) subgroups. RESULTS: Maternal sociodemographics (education level, marital status, nativity, and age at childbirth) had greater discriminating abilities in predicting ever XBR and XBR ≥ 6 months than birth outcomes and perinatal factors. Foreign-born women were two-fold more likely to initiate XBR but not necessarily continue to 6 months compared to their US-born counterparts. Factors associated with BrBot subgroups differed from those associated with XBR outcomes, whereas maternal age was the only predictor consistently associated with ever XBR, XBR ≥ 6 months, and BrBot subgroups. The areas under the receiver operating characteristic curves for models predicting ever XBR and XBR ≥ 6 months were 0.88 (95 % CI 0.85, 0.91) and 0.90 (95 % CI 0.88, 0.93), respectively. CONCLUSIONS: Findings underscore the importance of educational, clinical, and social support to promote XBR in mothers with sociodemographic factors predictive of none or poor XBR outcomes.