Completeness of protocols for clinical trials in children submitted to ethics committees.

AIM: Studies of published clinical trials involving children have shown frequent omissions in key aspects of design and conduct, but these problems may be artefactual and due to editorial processes and space limitations. To determine actual design and conduct, we analysed the completeness of key domains in trial protocols involving children submitted to Human Research Ethics Committees. METHODS: The ethics committees of all eight children's hospitals in Australia were invited to participate. De-identified trial protocols submitted for review in 2012 were evaluated using a checklist derived from Consolidated Standards of Reporting Trials, the Cochrane Risk of Bias Tool and Good Clinical Practice guidelines. RESULTS: Four ethics committees agreed to participate, and 69 protocols were analysed. The domains almost always reported were clustered around the background and trial plan (planned interventions for each group (99%), specific objectives (97%) and scientific background (96%)). Risk-of-bias domains such as random sequence generation and blinding of participants were often reported (75-90%). Domains least reported were clustered around the statistical analysis plan (66%), specified intention-to-treat analysis (54%), the justification for the proposed trial based upon a systematic review (48%) and age-specific outcomes (48%). CONCLUSIONS: Protocols of trials involving children assessed by ethics committees generally include details on background and basic design, but many key domains in trial design and conduct are not covered. Despite widespread recognition of how problems in the design and conduct of trials may lead to unreliable results, investigators still appear to be omitting key elements in trial protocols.

Disease burden-research match? Registered trials in child health from low- and middle-income and high-income countries.

AIM: The aim of this study was to determine whether there is a match between the health problems that children face and the clinical trials that are being conducted, especially in low- and middle-income countries (LMICs). METHODS: All trials on the World Health Organisation International Clinical Trials Registry Platform registered from 2005 to 2013 were reviewed. The disease-specific focus of registered trials for children was compared to the global burden of disease for 2011 using World Health Organisation disability-adjusted life-year data. RESULTS: Children account for 34% of the global disease burden, but were represented in only 15% (29 899/203 726) of registered trials. Although the number of trials in children registered annually has increased over time (from 3174 in 2005 to 3392 in 2013), the proportion of trials involving children has decreased (from 18 to 13%). LMICs account for 98% of the disease burden among children world-wide, but only 22% of trials. More trials were registered in high-income countries than in LMICs for the majority of the disease categories. There was moderate correlation between the number of trials and the burden of each disease within each region (Spearman's correlation r = 0.6, P = 0.007 and r = 0.55, P = 0.02 in LMICs and high-income countries, respectively). CONCLUSION: Overall, children continue to be under-represented in clinical trials, particularly children from LMICs where disease burden is greatest. Clinical trial activity correlates moderately with disease burden among the world's children. A more evidence-informed approach for prioritising trials to specifically address the health-care needs of children is required.

Researchers', Regulators', and Sponsors' Views on Pediatric Clinical Trials: A Multinational Study.

BACKGROUND AND OBJECTIVE: The last decade has seen dramatic changes in the regulatory landscape to support more trials involving children, but child-specific challenges and inequitable conduct across income regions persist. The goal of this study was to describe the attitudes and opinions of stakeholders toward trials in children, to inform additional strategies to promote more high-quality, relevant pediatric trials across the globe. METHODS: Key informant semi-structured interviews were conducted with stakeholders (researchers, regulators, and sponsors) who were purposively sampled from low- to middle-income countries and high-income countries. The transcripts were thematically analyzed. RESULTS: Thirty-five stakeholders from 10 countries were interviewed. Five major themes were identified: addressing pervasive inequities (paucity of safety and efficacy data, knowledge disparities, volatile environment, double standards, contextual relevance, market-driven forces, industry sponsorship bias and prohibitive costs); contending with infrastructural barriers (resource constraints, dearth of pediatric trial expertise, and logistical complexities); navigating complex ethical and regulatory frameworks ("draconian" oversight, ambiguous requirements, exploitation, excessive paternalism and precariousness of coercion versus volunteerism); respecting uniqueness of children (pediatric research paradigms, child-appropriate approaches, and family-centered empowerment); and driving evidence-based child health (advocacy, opportunities, treatment access, best practices, and research prioritization). CONCLUSIONS: Stakeholders acknowledge that changes in the regulatory environment have encouraged more trials in children, but they contend that inequities and political, regulatory, and resource barriers continue to exist. Embedding trials as part of routine clinical care, addressing the unique needs of children, and streamlining regulatory approvals were suggested. Stakeholders recommended increasing international collaboration, establishing centralized trials infrastructure, and aligning research to child health priorities to encourage trials that address global child health care needs.

Stakeholder Views of Clinical Trials in Low- and Middle-Income Countries: A Systematic Review.

CONTEXT: Clinical trials are necessary to improve the health care of children, but only one-quarter are conducted in the low- to middle-income countries (LMICs) in which 98% of the global burden of disease resides. OBJECTIVE: To describe stakeholder beliefs and experiences of conducting trials in children in LMICs. DATA SOURCES: Electronic databases were searched to August 2014. STUDY SELECTION: Qualitative studies of stakeholder perspectives on conducting clinical trials among children in LMICs. DATA EXTRACTION: Findingswere analyzed by using thematic synthesis. RESULTS: Thirty-nine studies involving 3110 participants (children [n = 290], parents or caregivers [n = 1609], community representatives [n = 621], clinical or research team members [n = 376], regulators [n = 18], or sponsors [n = 15]) across 22 countries were included. Five themes were identified: centrality of community engagement (mobilizing community, representatives' pivotal role, managing expectations, and retaining involvement); cognizance of vulnerability and poverty (therapeutic opportunity and medical mistrust); contending with power differentials (exploitation, stigmatization, and disempowerment); translating research to local context (cultural beliefs, impoverishment constraints, and ethical pluralism); and advocating fair distribution of benefits (health care, sponsor obligation, and collateral community benefits). LIMITATIONS: Studies not published in English were excluded. CONCLUSIONS: Conducting trials in children in LMICs is complex due to social disadvantage, economic scarcity, idiosyncratic cultural beliefs, and historical disempowerment, all of which contribute to inequity, mistrust, and fears of exploitation. Effective community engagement in recruiting, building research capacities, and designing trials that are pragmatic, ethical, and relevant to the health care needs of children in LMICs may help to improve the equity and health outcomes of this vulnerable population.

Clinical trials in children.

Safety and efficacy data on many medicines used in children are surprisingly scarce. As a result children are sometimes given ineffective medicines or medicines with unknown harmful side effects. Better and more relevant clinical trials in children are needed to increase our knowledge of the effects of medicines and to prevent the delayed or non-use of beneficial therapies. Clinical trials provide reliable evidence of treatment effects by rigorous controlled testing of interventions on human subjects. Paediatric trials are more challenging to conduct than trials in adults because of the paucity of funding, uniqueness of children and particular ethical concerns. Although current regulations and initiatives are improving the scope, quantity and quality of trials in children, there are still deficiencies that need to be addressed to accelerate radically equitable access to evidence-based therapies in children.

Effect of oral curcumin on Déjérine-Sottas disease.

Curcumin is the newest therapeutic agent for ameliorating the clinical and neuropathologic phenotype of a mouse model of Déjérine-Sottas disease. We undertook a 12-month dose-escalation safety trial of oral curcumin in a 15-year-old Caucasian girl with Déjérine-Sottas disease (point mutation, Ser72Leu) complicated by severe weakness, scoliosis, and respiratory impairment. The patient received 50 mg/kg/day oral curcumin for the first 4 months and 75 mg/kg/day thereafter, to complete a 12-month trial. Outcome measures included muscle strength, pulmonary function, upper/lower extremity disability, neurophysiologic studies, and health-related quality of life. After 12 months, the patient experienced no adverse events, and reported good compliance. There was little improvement in objective outcome measures. Knee flexion and foot strength increased slightly, but hand and elbow strength decreased. Pulmonary function, hand function, and measures of upper/lower extremity disability were stable or reduced. Her neurophysiologic findings were unchanged. Parent-reported quality of life improved for most domains, especially self-esteem, during the 12 months of treatment. Child-reported quality of life, assessed at the final visit, mirrored these results, with overall feelings of happiness and contentment. Further studies are required to explore the efficacy and safety of curcumin for severe demyelinating neuropathies of infancy and early childhood.

Ascorbic acid for Charcot-Marie-Tooth disease type 1A in children: a randomised, double-blind, placebo-controlled, safety and efficacy trial.

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited nerve disorder. CMT1A is characterised by peripheral nerve demyelination, weakness, and impaired motor function and is caused by the duplication of PMP22, the gene that encodes peripheral myelin protein 22. High-dose ascorbic acid has been shown to have remyelinating potential and to correct the phenotype of a transgenic mouse model of CMT1A by decreasing expression of PMP22. We tested the efficacy and safety of ascorbic acid supplementation in children with CMT1A. METHODS: This 12-month, randomised, double-blind, placebo-controlled trial undertaken between June, 2007, and December, 2008, assessed high-dose oral ascorbic acid (about 30 mg/kg/day) in 81 children with CMT1A (2-16 years). Randomisation was done on a 1:1 ratio by a computer-generated algorithm. All investigators and participants were blinded to treatment allocation with the exception of the trial pharmacist. The primary efficacy outcome was median nerve motor conduction velocity (m/s) at 12 months. Secondary outcomes were foot and hand strength, motor function, walking ability, and quality of life. Compliance was measured by plasma ascorbic acid concentration, pill count, and medication diary entries. Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, Number 12606000481572. FINDINGS: 81 children were randomly assigned to receive high-dose ascorbic acid (n=42) or placebo (n=39). 80 children completed 12 months of treatment. The ascorbic acid group had a small, non-significant increase in median nerve motor conduction velocity compared with the placebo group (adjusted mean difference 1.7 m/s, 95% CI -0.1 to 3.4; p=0.06). There was no measurable effect of ascorbic acid on neurophysiological, strength, function, or quality of life outcomes. Two children in the ascorbic acid group and four children in the placebo group reported gastrointestinal symptoms. There were no serious adverse events. INTERPRETATION: 12 months of treatment with high-dose ascorbic acid was safe and well tolerated but none of the expected efficacy endpoints were reached.