Pediatric Drug Trials Research Articles

Current Status of Pharmacokinetic Research in Children: A Systematic Review of Clinical Trial Records.

Many medications have different pharmacokinetics in children than in adults. Knowledge about the safety and efficacy of medications in children requires research into the pharmacokinetic profiles of children's medicines. By analysing registered clinical trial records, this study determined how frequently pharmacokinetic data is gathered in paediatric drug trials. We searched for the pharmacokinetic data from clinical trial records for preterm infants and children up to the age of 16 from January 2011 to April 2022. The records of trials involving one or more drugs in preterm infants and children up to the age of 16 were examined for evidence that pharmacokinetic data would be collected. In a total of 1483 records of interventional clinical trials, 136 (9.17%) pharmacokinetic data involved adults. Of those 136 records, 60 (44.1%) records were pharmacokinetics trials involving one or more medicines in children up to the age of 16. 20 (33.3 %) in America, followed by 19 (31.6 %) in Europe. Most trials researched medicines in the field of infection or parasitic diseases 20 (33.3%). 27 (48.2%) and 26 (46.4%) trials investigated medicines that were indicated as essential medicine. The pharmacokinetic characteristics of children's drugs need to be better understood. The current state of pharmacokinetic research appears to address the knowledge gap in this area adequately. Despite slow progress, paediatric clinical trials have experienced a renaissance as the significance of paediatric trials has gained international attention. The outcome of paediatric trials will have an impact on children's health in the future. In recent years, the need for greater availability and access to safe child-size pharmaceuticals has received a lot of attention.

What information and the extent of information to be provided in an informed assent/consent form of pediatric drug trials

BackgroundThis study aimed to determine the elements and the extent of information that child participants and their parents would like to read in an informed assent form (IAF)/informed consent form (ICF) of a pediatric drug trial.MethodsA descriptive survey was conducted to determine the perceived importance of each element of the ICF content from child participants and their parents who underwent informed assent/consent of a multi-center pediatric drug trial. The respondents were asked to indicate the level of importance of each item in a questionnaire, by giving a rating scale from 1 (not important) to 5 (very important).ResultsA total of 22 families, 17 child participants with the diagnosis of hematology or oncology diseases and 27 parents, were enrolled. Among 30 items, risk–benefit aspects (i.e., direct health benefit [mean: 4.71 for child respondents, 4.89 for parent respondents], indirect/societal benefit [mean: 4.65, 4.85], major foreseeable risk [mean: 4.47, 4.78], post-trial benefit/provision [mean: 4.59, 4.74], and all adverse effects of the drug including uncommon adverse effects [mean: 4.53, 4.74]) were perceived to be of most concerning items from both child participants’ and parents’ viewpoint. None of the items were considered ‘slightly important’ or lower by more than 20% of the respondents.ConclusionsFor pediatric drug trials, risk–benefit information (including direct health benefit, indirect/societal benefit, and post-trial benefit/provision, as well as major foreseeable risk and adverse effects of the drug) should be made a salient feature of an IAF/ICF. This empirical data could help related stakeholders arrange essential information in order of importance and tailor an IAF/ICF to better suit child participants’ and parents’ needs, particularly for pediatric drug trials involving children with the diagnosis of hematology or oncology diseases.

Data-Driven Approaches to Maximize the Impact of Pediatric Clinical Trials.

Data-Driven Approaches to Maximize the Impact of Pediatric Clinical Trials.

Assessment of left ventricular dyssynchrony by speckle tracking echocardiography in children with Duchenne muscular dystrophy

Prognosis of Duchenne muscular dystrophy (DMD) is related to cardiac dysfunction. Two dimensional-speckle tracking echocardiography (2D-STE) has recently emerged as a non-invasive functional biomarker for early detection of DMD-related cardiomyopathy. This study aimed to determine, in DMD children, the existence of a left ventricle (LV) dyssynchrony using 2D-STE analysis. This prospective controlled study enrolled 25 boys with DMD (mean age 11.0 ± 3.5 years) with normal LV ejection fraction and 50 age-matched controls. Three measures were performed to assess LV mechanical dyssynchrony: the opposing-wall delays (longitudinal and radial analyses), the modified Yu index, and the time-to-peak delays of each segment. Feasibility and reproducibility of 2D-STE dyssynchrony were evaluated. All three mechanical dyssynchrony criteria were significantly higher in the DMD group than in healthy subjects: – opposing-wall delays in basal inferoseptal to basal anterolateral segments (61.4 ± 45.3 msec vs. 18.3 ± 50.4 msec, P < 0.001, respectively) and in mid inferoseptal to mid anterolateral segments (58.6 ± 35.3 msec vs. 42.4 ± 36.4 msec, P < 0.05, respectively); – modified Yu index (33.3 ± 10.1 msec vs. 28.5 ± 8.1 msec, P < 0.05, respectively); – most of time-to-peak values, especially in basal and mid anterolateral segments. Feasibility was excellent and reliability was moderate to excellent, with ICC values ranging from 0.49 to 0.97 ( Fig. 1 ). Detection of LV mechanical dyssynchrony using 2D-STE analysis is an easily and reproducible method in pediatrics. The existence of an early LV mechanical dyssynchrony visualized using 2D-STE analysis in children with DMD before the onset of cardiomyopathy represents a perspective for future pediatric drug trials in the DMD-related cardiomyopathy prevention.

First manifestation and evolution of early left ventricular dysfunction in children with Duchenne muscular dystrophy

Background: Standard pediatric cardiology examinations and echocardiography fail to discover when the cardiomyopathy will occur in patient with Duchenne muscular dystrophy (DMD). Noninvasive markers are needed to fill this gap. Material and methods: This cohort study included a total number of 30 children (21 children (70%) with DMD and 9 (30%) healthy children. Blood samples were used for biochemical (level of creatine kinase, creatine kinase-MB, lactate dehydrogenase) and miRNA (presence of miR133a 3p, miR133b 3p, miR206 3p, miR208a 3p, miR208b 3p) analysis. All patients underwent partial conventional echocardiography ECOCG and Speckle Tracking. Results: The children in the working group presented compared to healthy children: FCC values increased by 15 (71%) vs 2 (22%), high levels of CK, CK-MB, LDH, which is characteristic for the disease and reflects its stage. Also, there is a decrease in systolic function indicators in the working group: mean FE 59 ± 3.8 %, and GLS: -16.2 ± 3.1%. MiRNA analyses confirmed the presence of miR133a 3p, miR133b 3p, miR206 3p, miR208a 3p, miR208b 3p in both working and control group. Conclusions: For the first time in the Republic of Moldova, we developed and adapted protocols for RNA extraction from human blood, performing screening of specific miRNA in the serum of patients with DMD and healthy children. Also, altered LV strain notwithstanding a normal or mildly modified LVEF represents an essential viewpoint for prospective pediatric drug trials in DMD-related cardiomyopathy prevention.

Deferred Consent in Pediatric Drug Trials: Moving from Why to How.

Deferred Consent in Pediatric Drug Trials: Moving from Why to How.

Evaluation of Publication of Pediatric Drug Trials

Evaluation of Publication of Pediatric Drug Trials

Current status of registered drug and vaccine pediatric clinical trials in China

Objective: To evaluate the current status of the registered pediatric drug or vaccine clinical trials in China for the purpose of providing a reference for the development of pediatric clinical trials in China. Methods: We collected the data about registered pediatric clinical trials that were conducted from September 6, 2013(Mandatory registration start date) to September 6, 2019 (Cut-off date) at Chinadrugtrials.org.cn platform. The survey items included trial name and number, drug classification, sponsor's information, current trial status, completion status, etc. The clinical trials were categorized by drug group (includes chemical medicine, traditional Chinese medicine and natural medicine, biological products) and by vaccine group. Results: During the six years 349 pediatric clinical trials were registered on the platform, including 162 pediatric drug trials and 187 vaccine trials. The numbers of chemical drugs and biological products registered in 2018 were 23 and 11, respectively, the highest in the history. The number of pediatric clinical trials of traditional Chinese medicine and natural medicine was 11 in 2014, but from 2015 to 2018 only 2 to 4 trials were registered each year. The overall completion rates of the registered drug and vaccine clinical trials were 22.8% (37/162) and 41.7%(78/187), respectively. Only 42 international multicenter pediatric clinical trial projects were registered on the platform. The numbers of drug and vaccine phase Ⅰ clinical trials were 4 and 46, respectively. Thirty-six pediatric endocrine system agent clinical trials were carried out, with the largest number of all the drug categories registered on the platform. Conclusions: In recent years the number of registered pediatric drug and vaccine clinical trials increased in China. However, the number is still very limited. It is urgent to further promote the development of pediatric clinical trials.

Family Perspectives on Clinical Research for Pediatric Multiple Sclerosis: Enhancing Equity.

Pediatric new drug trials are federally mandated, but family perspectives in multiple sclerosis (MS) research are limited. Due to MS chronicity and long-term medical system involvement, we obtained family views on research priorities and optimized methods for future studies. Focus groups were convened with families impacted by pediatric-onset MS. Recruitment included those followed by the Network of Pediatric MS Centers, geographically disparate locations, and centers’ voluntary election. Study questions included: healthcare experiences, clinical trials perspectives, cognitive/psychosocial/educational outcomes, disease course and disability accrual. All subjects supported future clinical studies. Patients highlighted contribution to knowledge base but were wary of experimental medication and disease-course impeding activities. Parents underscored medication delivery modalities, side-effects, and limiting children’s discomfort. All wanted study relevance made explicit. Suggested future study design elements included: providing compensation, limiting assumptions regarding outcome linkages, understanding study-related psychological impacts, and reducing participation burdens. Rare disease research can assist general medicine diagnosis and referral. Variable study designs and explicit rationale may augment participation. Closing the pediatric research gap requires family engagement in the research process.

Trends in prescribing anti-obesity pharmacotherapy for paediatric weight management: Data from the POWER Work Group.

To better inform the field of obesity medicine, we set out to describe the current use of pharmacotherapy meant to improve patient weight status among a group of clinicians connected through the Paediatric Obesity Weight Evaluation Registry (POWER), as well as reasons behind clinicians' use or non-use of the medications. Paediatric weight management (PWM) programs participating in POWER were asked to complete a program profile survey in 2014 (n = 30) and 2017 (n = 33); questions about pharmacotherapy use were included. Descriptive statistics were used to identify: (a) the proportion of PWM programs offering obesity pharmacotherapy; (b) the medications most commonly prescribed; and (c) reasons among non-prescribers for not offering pharmacotherapy. The 2014 and 2017 surveys were completed by 29 PWM programs (97%) and 30 PWM programs (91%), respectively. Twenty-one programs completed both surveys. In 2014, 10 (34%) programs reported offering pharmacologic agents specifically for weight control, whereas in 2017, 16 (53%) reported offering pharmacotherapy for a primary indication of weight loss. Metformin was reported as the most commonly used agent in 2014, and topiramate in 2017. Largest reported increases in use over time were for topiramate and phentermine. Our survey results demonstrate that a majority of this group of PWM programs offered pharmacotherapy to promote weight loss in patients with complications or associated medical conditions. There was a trend indicating increasing use over time, despite the significant gap regarding pharmacotherapy use in the literature. These data suggest the need for (a) additional robust paediatric drug trials to further develop the evidence base guiding use or non-use of pharmacotherapy in paediatric weight management, and (b) increased understanding of both facilitators and barriers to prescribing anti-obesity pharmacotherapy for youth with obesity.

Implementing a Clinical Research Department to Support Pediatric Studies: A SWOT Analysis.

The safety, tolerability, pharmacokinetics and efficacy of most drugs used in pediatrics have not been studied in different age groups and are administered “off-label use”. Clinical pediatric drug trials require specific and stringent compliance with laws, regulations, guidelines, and patient/parent/public involvement, which in turn increases resource use and makes support useful from a medical, qualitative, economic, and system perspective. We examined the strengths, weaknesses, opportunities and threats of implementing a Research Department for the Support of Pediatric Studies (RDPS) in Vienna. We used the SWOT (“strengths”, “weaknesses”, “opportunities”, and “threats”) analysis to collect comprehensive data and facts on the internal strengths, weaknesses (company analysis), and external opportunities and threats (environmental analysis). The company analysis revealed a productivity gain, due to a highly specialized team and standardized processes. The environmental analysis outlined a considerable 360-degree potential for a qualitative and quantitative medical- and social-scientific expansion of the service portfolio. The establishment of a RDPS leads to the centralization of pediatric studies by bundling tasks and concentration of specialist knowledge, which enables the exploitation of synergies, the standardization of processes, the promotion of professionalism, flexibility, innovations and the reduction of inefficiencies in the form of duplication of tasks. RDPS offers tailored advice and support for different types of pediatric studies.

Paediatric drugs trials in China

ObjectiveClinical trials of children’s drugs are of great significance to rational drug use in children. However, paediatric drugs trials in China are facing complex challenges. At present, the investigation data...

A multi-national trial of a direct oral anticoagulant in children with cardiac disease: Design and rationale of the Safety of ApiXaban On Pediatric Heart disease On the preventioN of Embolism (SAXOPHONE) study

Anticoagulation in children is problematic for multiple reasons. Currently used anticoagulants have significant disadvantages and may negatively affect quality of life (QOL). This manuscript describes the design, rationale, and methods of a prospective, randomized, open label phase II multi-national clinical trial of a direct oral anticoagulant (DOAC), apixaban, in children and infants with congenital and acquired heart disease. This trial is designed to gather preliminary safety and pharmacokinetics (PK) data, as well as generate data on QOL of individuals taking apixaban compared to the standard of care (SOC) anticoagulants vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). A key issue this trial seeks to address is the practice of using therapeutics tested in adult trials in the pediatric population without robust pediatric safety or efficacy data. Pediatric heart diseases are not common, and specific diagnoses often meet the criteria of a rare disease; thus, statistical efficacy may be difficult to achieve. This trial will provide valuable PK and safety data intended to inform clinical practice for anticoagulation in pediatric heart diseases, a setting in which a fully powered phase III clinical trial is not feasible. A second consideration this trial addresses is that metrics besides efficacy, such as QOL, have not been traditionally used as endpoints in regulated anticoagulation studies yet may add substantial weight to the clinical decision for use of a DOAC in place of VKA or LMWH. This study examines QOL related to both heart disease and anticoagulation among children randomized to either SOC or apixaban. There are considerable strengths and benefits to conducting a clinical trial in pediatric rare disease populations via an industry-academic collaboration. The SAXOPHONE study represents a collaboration between Bristol-Myers Squibb (BMS)/Pfizer Alliance, and the National Heart, Lung, and Blood Institute's (NHLBI) Pediatric Heart Network (PHN) and may be an attractive model for future pediatric drug trials.

Neglected tropical diseases in children: An assessment of gaps in research prioritization.

BackgroundDespite the known burden of neglected tropical diseases (NTDs) on child health, there is limited information on current efforts to increase pediatric therapeutic options. Our objective was to quantify and characterize research activity and treatment availability for NTDs in children in order to inform the prioritization of future research efforts.Methodology/Principal findingsWe conducted a review of the World Health Organization’s (WHO) International Clinical Trials Registry Platform to assess research activity for NTDs. The burden of disease of each NTD was measured in terms of disability adjusted life years (DALYs), which was extracted from the Global Health Data Exchange. First- and second-line medications for each NTD were identified from WHO guidelines. We reviewed FDA drug labels for each medication to determine whether they were adequately labeled for use in children. Descriptive statistics, binomial tests, and Spearman’s rank order correlations were calculated to assess research activity compared to burden of disease. Children comprised 34% of the 20 million DALYs resulting from NTDs, but pediatric trials contributed just 17% (63/369) of trials studying these conditions (p<0.001 for binomial test). Conditions that were particularly under-represented in pediatric populations compared to adults included rabies, leishmaniasis, scabies, and dengue. Pediatric drug trial activity was poorly correlated with pediatric burden of disease across NTDs (Spearman’s rho = 0.41, p = 0.12). There were 47 medications recommended by the WHO for the treatment of NTDs, of which only 47% (n = 22) were adequately labeled for use in children. Of the 25 medications lacking adequate pediatric labeling, three were under study in pediatric trials.Conclusions/SignificanceThere is a substantial gap between the burden of disease for NTDs in children and research devoted to this population. Most medications lack adequate pediatric prescribing information, highlighting the urgency to increase pediatric research activity for NTDs with high burden of disease and limited treatment options.

Speckle-Tracking Echocardiography in Children With Duchenne Muscular Dystrophy: A Prospective Multicenter Controlled Cross-Sectional Study

Prognosis of Duchenne muscular dystrophy (DMD) is related to cardiac dysfunction. Speckle-tracking echocardiographic (STE) imaging is emerging as a noninvasive functional biomarker to consider in the early detection of DMD-related cardiomyopathy. However, STE analysis has not been assessed in a prospectively controlled study, especially in presymptomatic children with DMD, and no study has used STE analysis in all three displacements (longitudinal, radial, and circumferential) and for both ventricles. This prospective controlled study enrolled 108 boys, 36 of whom had DMD (mean age, 11±3.8years) and 72 of whom were age-matched control subjects in a 1:2 case-control design. Conventional echocardiographic variables were collected for the left and right ventricles. STE analyses were performed in the longitudinal, radial, and circumferential displacements for the left ventricle and in the free wall longitudinal displacement for the right ventricle. The effect of age on the evolution of two-dimensional strain in children with DMD was studied by adding an interaction term, DMD×age, in the models. Conventional echocardiographic measures were normal in both groups. Left ventricular (LV) ejection fraction ranged from 45% to 76% (mean, 63±6%) in the DMD group and from 55% to 76% (mean, 64±5%) in the control group. Global LV strain mean measures were significantly worse in the DMD group for the longitudinal (-16.8±3.9% vs -20.6±2.6%, P<.0001), radial (22.7±11.3% vs 31.7±14%, P=.002), and circumferential (-16.5±3.8% vs -20.3±3.1%, P<.0001) displacements. The decrease of global LV longitudinal strain with age in children with DMD was 0.34% per year more marked than that in control subjects. The LV inferolateral and anterolateral segments were specifically impaired, especially in the basal area. Right ventricular function evaluated using conventional echocardiography and STE analysis was normal and not different between children with DMD and control subjects. The existence of altered LV strain despite normal LV function in children with DMD represents an important perspective for future pediatric drug trials in DMD-related cardiomyopathy prevention.

Ethical considerations of researchers conducting pediatric clinical drug trials: a qualitative survey in two Belgian university children's hospitals.

We argue for constant ethical reflexivity in pediatric clinical trials, because broad ethical principles are not always easy to apply to specific situations. What is Known: • Several international guidelines and a large body of scientific literature indicate a broad consensus about the basic ethical framework for pediatric clinical trials, based on risk benefit assessment and respect for autonomy. • Little is known about how researchers implement these broad principles in practice. What is New: • Researchers' risk/benefit assessments about their own studies resembled the assessment of neutral peers, assessing burden was more subjective. • Researchers were very confident in their ability to obtain valid informed consent.

Facilitators and barriers to the successful implementation of pediatric antibacterial drug trials: Findings from CTTI's survey of investigators.

An urgent need exists to develop new antibacterial drugs for children. We conducted research with investigators of pediatric antibacterial drug trials to identify facilitators and barriers in the conduct of these trials. Seventy-three investigators completed an online survey assessing the importance of 15 facilitators (grouped in 5 topical categories) and the severity of 36 barriers (grouped in 6 topical categories) to implementing pediatric antibacterial drug trials. Analysis focused on the identification of key factors that facilitate the successful implementation of pediatric antibacterial drug trials and the key barriers to implementation. Almost all investigators identified two factors as very important facilitators: having site personnel for enrollment and having adequate funding. Other top factors were related to staffing. Among the barriers, factors related to parent concerns and consent were prominent, particularly obtaining parental consent when there was disagreement between parents, concerns about the number of blood draws, and concerns about the number of invasive procedures. Having overly narrow eligibility criteria was also identified as a major barrier. The survey findings suggest three areas in which to focus efforts to help facilitate ongoing drug development: (1) improving engagement with parents of children who may be eligible to enroll in a pediatric antibacterial drug trial, (2) broadening inclusion criteria to allow more participants to enroll, and (3) ensuring adequate staffing and establishing sustainable financial strategies, such as funding pediatric trial networks. The pediatric antibacterial drug trials enterprise is likely to benefit from focused efforts by all stakeholders to remove barriers and enhance facilitation.

Methodological and Ethical Issues in Pediatric Medication Safety Research.

In May 2016, the Eshelman School of Pharmacy at The University of North Carolina at Chapel Hill convened the PharmSci conference to address the topic of "methodological and ethical issues in pediatric medication safety research." A multidisciplinary group of experts representing a diverse array of perspectives, including those of the US Food and Drug Administration, children's hospitals, and academia, identified important considerations for pediatric medication safety research and opportunities to advance the field. This executive summary describes current challenges that clinicians and researchers encounter related to pediatric medication safety research and identifies innovative and ethically sound methodologies to address these challenges to improve children's health. This article addresses 5 areas: (1) pediatric drug development and drug trials; (2) conducting comparative effectiveness research in pediatric populations; (3) child and parent engagement on study teams; (4) improving communication with children and parents; and (5) assessing child-reported outcomes and adverse drug events.

2017 ACC/AAP/AHA Health Policy Statement on Opportunities and Challenges in Pediatric Drug Development: Learning From Sildenafil.

T he STARTS-1 and -2 trials (Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension) and subsequent 2012 US Food and Drug Administration (FDA) product labeling for sildenafil use in pediatric patients with pulmonary hypertension highlight many of the challenges to the development and approval of medications for children. This experience served as the impetus for direct collaboration between FDA representatives and the Joint Council on Congenital Heart Disease (JCCHD) (representing the pediatric cardiology leadership of the American College of Cardiology, the American Heart Association, and the American Academy of Pediatrics) to improve communication and realign missions with regard to pediatric drug trials. These discussions led to the joint FDA/JCCHD development of this statement, which describes the current environment and identifies possible future directions for reducing barriers to pediatric drug trials. There are many challenges to the development and approval of medications for children. The STARTS-1 and -2 trials, which are described briefly in the next section, highlight many of the challenges in pediatric trial design and approval of medications for children, especially those with rare diseases. Through a series of conversations between the FDA and JCCHD that had their origin around review of the effect of the STARTS-1 and -2 trials and subsequent regulatory response on clinical practice, it became clear that better communication and alignment of goals surrounding pediatric drug trials were needed. This paper serves as unique opportunity to bring leaders of the pediatric cardiology community and FDA together as 1 voice. Fewer than 50% of drugs approved for use in the United States have sufficient data to support labeling for dosing, safety, and efficacy in children.1,2 Several studies estimate at least 40% and up to 100% of hospitalized children are prescribed at least 1 medication that is used “off-label.”3 …

Perspectives in pediatric clinical trials: a review

&lt;p class="abstract"&gt;Children are different from adults in many aspects of pharmacotherapy, including capacity to absorb, distribute, metabolize and excrete drugs and have their own taste preferences. International Conference on Harmonisation (ICH) guidelines classify pediatric age groups into five groups namely preterm, term new born infants, infants and toddlers, children and adolescents. United States conducts maximum number of pediatric drug trials as compared to developing countries. Most of the prescribed drugs are either unlicensed or have an off label use. That is these have not been evaluated for their safety and efficacy in children. As children are separate population entity and not mini-adults, these clinical trials with adults cannot be simply generalized or extrapolated to pediatric population. Thus it is mandatory to conduct clinical trials involving pediatric population in order to get full benefits to the children. To study this gap between adults and children for their wellbeing, disease prevention, diagnosis and treatment, high quality clinical trials are required&lt;span lang="EN-US"&gt;.&lt;/span&gt;&lt;/p&gt;