A Decade of Efforts to Add Value to Child Health Research Practices.

OBJECTIVE: To identify practices that add value to improve the design, conduct, and reporting of child health research and reduce research waste. STUDY DESIGN: In order to categorize the contributions of members of Standards for Research (StaR) in Child Health network, we developed a novel Child Health Improving Research Practices (CHIRP) framework comprised of 5 domains meant to counteract avoidable child health research waste and improve quality: 1) address research questions relevant to children, their families, clinicians, and researchers; 2) apply appropriate research design, conduct and analysis; 3) ensure efficient research oversight and regulation; 4) Provide accessible research protocols and reports; and 5) develop unbiased and usable research reports, including 17 responsible research practice recommendations. All child health research relevant publications by the 48 original StaR standards' authors over the last decade were identified, and main topic areas were categorized using this framework. RESULTS: A total of 247 publications were included in the final sample: 100 publications (41%) in domain 1 (3 recommendations), 77 publications (31%) in domain 2 (3), 35 publications (14%) in domain 3 (4), 20 publications (8%) in domain 4 (4), and 15 publications (6%) in domain 5 (3). We identified readily implementable "responsible" research practices to counter child health research waste and improve quality, especially in the areas of patients and families' engagement throughout the research process, developing Core Outcome Sets, and addressing ethics and regulatory oversight issues. CONCLUSION: While most of the practices are readily implementable, increased awareness of methodological issues and wider guideline uptake is needed to improve child health research. The CHIRP Framework can be used to guide responsible research practices that add value to child health research.

A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials.

Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.

Guidance on development and operation of Young Persons' Advisory Groups.

BACKGROUND: Engaging patients and the public as collaborators in research is increasingly recognised as important as such partnerships can help improve research relevance and acceptability. Young Persons' Advisory Groups (YPAGs) provide a forum for clinical researchers and triallists to engage with children and young people on issues relevant to the design, conduct and translation of paediatric clinical trials. Until fairly recently, there was very little information available to guide the successful development and operation of YPAGs. OBJECTIVE: To develop an evidence-based tool to guide clinical researchers and triallists in the establishment and operation of a YPAG. METHODS: An online needs assessment survey was conducted using SurveyMonkey with 60 known paediatric drug researchers to identify knowledge gaps around YPAG engagement, development and operation. Semistructured interviews with founders and coordinators of five well-established existing YPAGs and a review of the literature were performed to identify best-practice processes for starting up and operating YPAG. RESULTS: The majority of 12 survey respondents (20%) from 12 different centres indicated that while they felt YPAGs could benefit their research, guidance on how to develop and operate a YPAG was needed. Most preferred a web-based guidance tool. Ten core steps in starting up and operating a YPAG were identified and developed into an online YPAG guidance tool, now freely accessible for use by paediatric clinical researchers worldwide. Plans to evaluate the impact are in place. CONCLUSIONS: This novel tool, developed with an internationally based group of public involvement leads working across paediatric clinical research areas, provides harmonised guidance for researchers seeking to develop and operate YPAGs to help improve the quality and impact of paediatric clinical research studies.

Innovative approaches to investigator-initiated, multicentre paediatric clinical trials in Canada.

Data from clinical trials are needed to guide the safe and effective use of medicines in children. Clinical trials are challenging to design and implement in all populations, and children present additional considerations. Several regions including the UK, USA and Europe have established clinical trial infrastructure to capitalise on expertise and promote clinical trials enrolling children. Our objective is to describe the partnerships and operational considerations for the development of paediatric clinical trials infrastructure in Canada. We describe the design and conduct of four emergency room paediatric trials, with four separate sponsors, across four provinces in parallel. Operations discussed include multisite contract development, centralised risk-based data monitoring, ethical review and patient engagement. We conclude with lessons learnt, additional challenges and potential solutions to facilitate drug development for children in Canada.

Important differences in management policies for children with end-stage renal disease in the Netherlands and Belgium--report from the RICH-Q study.

BACKGROUND: The low prevalence of childhood end-stage renal disease and the small centre sizes have been a barrier for clinical studies and the development of evidence-based guidelines for chronic renal replacement therapy (cRRT) in children. Few data exist on the quality of care for these patients and the applicability of existing guidelines. The aim of this study is to quantify variation in treatment policies and actually delivered care in nine centres that deliver cRRT for children. METHODS: We surveyed treatment policies in all nine centres in the Netherlands and Belgium and compared them with the actually provided therapies and with recommendations from available guidelines. Data on treatment policies were gathered by questionnaires; actually provided care and outcomes were registered prospectively from 2007 to 2010. RESULTS: Data on policies and actual patient care were obtained from all nine centres. We found relevant differences between centres in treatment policies on various topics, e.g. estimated glomerular filtration rate threshold as an indication for initiation of cRRT, preferred initial mode of cRRT, peritoneal dialysis catheter care, haemodialysis frequency and vascular access. Discrepancies were seen between stated treatment policies and actual performed therapies. For the majority of policies, no evidence-based guidelines are available. CONCLUSIONS: Health care disparities exist due to large and unwanted variation in treatment policies between hospitals providing cRRT for children. Delivered care does not live up to stated policies, for which clear and internationally accepted guidelines are lacking.

Towards evidence-based pharmacotherapy in children.

In daily practice, it is difficult to find a registered drug for children, because about 70% of the drugs prescribed in children are not studied, off-label or unlicensed in this age group. Clinical trials have usually been performed in adults, and then in daily practice dosages are adjusted for children without proper studies in that age group. In some countries, national formularies are being established to overcome the existing variance in prescribing between physicians. Complicating factors in finding the correct dosage for children include the heterogeneity between different age groups in the developmental stages of the organs influencing the absorption, distribution, metabolism, and excretion as well as differences in body composition during growth. Growth may also influence the effects and adverse effects of a drug used in a child. For oral administration of drugs in children, the bioavailability, the taste, the composition, and the absence of toxic ingredients for that age group are additional important factors. The EU has recently introduced legislation to stimulate the pharmaceutical industry to investigate the pharmacological effect and safety of new medicines in children. In response to this legislation, research networks are being established to provide the optimal infrastructure for pediatric drug investigation. The goals of this paper are to review the current problems in daily practice and to address the needs for evidence based pharmacotherapy in children.

Implementation of an evidence-based guideline on fluid resuscitation: lessons learnt for future guidelines.

INTRODUCTION: There is little experience with the nationwide implementation of an evidence-based pediatric guideline on first-choice fluid for resuscitation in hypovolemia. METHODS: We investigated fluid prescribing behavior at (1) guideline development, (2) after guideline development, and (3) after active implementation and identified potential barriers and facilitators for guideline implementation. In order to minimize costs and to optimize implementation effect, we continuously developed and adjusted implementation strategies according to identified barriers. Implementation success was evaluated using questionnaires, pharmaceutical data, and data from medical records. DISCUSSION: The most remarkable change occurred after guideline development and dissemination: Normal saline use by neonatologists increased from 22-89% to 100% and by pediatric intensivists from 43-71% to 88-100%, and synthetic colloid use by pediatric intensivists declined from 29-43% to 0-13% with a reduction in albumin use by neonatologists from 11-44% to 0%. After active guideline implementation, most of specialist's management behavior was according to the guideline. CONCLUSION: Stakeholders involved in the developmental process are of great importance in disseminating recommendations before active implementation. Therefore, to successfully implement guidelines and reduce costs of active implementation, any guideline development should consider implementation right from the beginning. Implementation strategies should target identified barriers and will therefore always be guideline specific.

IVF with preimplantation genetic screening, a promising new treatment with unexpectedly negative health outcomes: the Hippocratic role of Data Monitoring Committees.

A recently published randomized controlled trial showed preimplantation genetic screening (PGS) as part of an IVF programme to reduce ongoing pregnancy rates by 1/3 in comparison to the control group without PGS: rate ratio (RR) 0.69 (0.51-0.93), P = 0.01. A masked interim analysis already showed significant differences between treatment arms: RR 0.58 (0.35-0.94), P = 0.02. Despite this finding, the trial's Data Monitoring Committee decided not to stop, but to continue the trial. This paper argues why this decision was sound, since it was based on (i) explicit statistical criteria and (ii) the trade-off between risks and benefits for current and future IVF patients. The trial's findings confront the medical community once again with the general problem of new technologies being implemented without randomized evidence of effectiveness.