Robert Phillips

Increasing value and reducing waste in biomedical research regulation and management

After identification of an important research question and selection of an appropriate study design, waste can arise from the regulation, governance, and management of biomedical research. Obtaining regulatory and governance approval has become increasingly burdensome and disproportionate to the conceivable risks to research participants. Regulation and governance involve interventions that are assumed to be justified in the interests of patients and the public, but they can actually compromise these interests. Inefficient management of the procedural conduct of research is wasteful, especially if it results in poor recruitment and retention of participants in well designed studies addressing important questions. These sources of waste can be minimised if the following four recommendations are addressed. First, regulators should use their influence to reduce other causes of waste and inefficiency in research. Second, regulators and policy makers should work with researchers, patients, and health professionals to streamline and harmonise the laws, regulations, guidelines, and processes that govern whether and how research can be done, and ensure that they are proportionate to the plausible risks associated with the research. Third, researchers and research managers should increase the efficiency of recruitment, retention, data monitoring, and data sharing in research through use of research designs known to reduce inefficiencies, and further research should be done to learn how efficiency can be increased. Finally, everyone, particularly those responsible for health-care systems, should promote integration of research into everyday clinical practice. Regulators and researchers should monitor adherence to each of these recommendations and publish metrics.

Systematic review and meta-analysis of the value of initial biomarkers in predicting adverse outcome in febrile neutropenic episodes in children and young people with cancer

BackgroundFebrile neutropenia is a frequently occurring and occasionally life-threatening complication of treatment for childhood cancer. Many biomarkers have been proposed as predictors of adverse events. We aimed to undertake a systematic review and meta-analysis to summarize evidence on the discriminatory ability of initial serum biomarkers of febrile neutropenic episodes in children and young people.MethodsThis review was conducted in accordance with the Center for Reviews and Dissemination Methods, using three random effects models to undertake meta-analysis. It was registered with the HTA Registry of systematic reviews, CRD32009100485.ResultsWe found that 25 studies exploring 14 different biomarkers were assessed in 3,585 episodes of febrile neutropenia. C-reactive protein (CRP), pro-calcitonin (PCT), and interleukin-6 (IL6) were subject to quantitative meta-analysis, and revealed huge inconsistencies and heterogeneity in the studies included in this review. Only CRP has been evaluated in assessing its value over the predictive value of simple clinical decision rules.ConclusionsThe limited data available describing the predictive value of biomarkers in the setting of pediatric febrile neutropenia mean firm conclusions cannot yet be reached, although the use of IL6, IL8 and procalcitonin warrant further study.

Updated systematic review and meta-analysis of the performance of risk prediction rules in children and young people with febrile neutropenia.

Introduction Febrile neutropenia is a common and potentially life-threatening complication of treatment for childhood cancer, which has increasingly been subject to targeted treatment based on clinical risk stratification. Our previous meta-analysis demonstrated 16 rules had been described and 2 of them subject to validation in more than one study. We aimed to advance our knowledge of evidence on the discriminatory ability and predictive accuracy of such risk stratification clinical decision rules (CDR) for children and young people with cancer by updating our systematic review. Methods The review was conducted in accordance with Centre for Reviews and Dissemination methods, searching multiple electronic databases, using two independent reviewers, formal critical appraisal with QUADAS and meta-analysis with random effects models where appropriate. It was registered with PROSPERO: CRD42011001685. Results We found 9 new publications describing a further 7 new CDR, and validations of 7 rules. Six CDR have now been subject to testing across more than two data sets. Most validations demonstrated the rule to be less efficient than when initially proposed; geographical differences appeared to be one explanation for this. Conclusion The use of clinical decision rules will require local validation before widespread use. Considerable uncertainty remains over the most effective rule to use in each population, and an ongoing individual-patient-data meta-analysis should develop and test a more reliable CDR to improve stratification and optimise therapy. Despite current challenges, we believe it will be possible to define an internationally effective CDR to harmonise the treatment of children with febrile neutropenia.

A systematic review of time to diagnosis in children and young adults with cancer

Purpose It is often assumed that prolonged time to diagnosis (TTD) for cancer negatively influences overall survival and survivorship through advanced stage disease at diagnosis. This systematic review assesses existing early diagnosis research in childhood and young adult cancer and aims to identify whether a consensus exists within the literature in relation to the terminology and methodologies used to investigate TTD in this population. Methods Medline, Embase, the Centre for Reviews and Dissemination database and Cochrane library were searched for papers on children and young adults (0–30 years) published from 1948 to the present. Results Of the 1665 potentially eligible citations identified, 32 papers met the inclusion criteria. The majority of work was in European (n=15) or North American (n=8) populations. Most work focused on brain tumours (n=10), retinoblastomas (n=5) and bone and soft tissue sarcomas (n=4). The majority of studies were in hospital-based settings (n=25), with only seven papers adopting a population-based setting. Summary statistics presented were mostly median TTD, the skewed distribution of the data meant comparisons between studies based on medians were difficult and combining studies within a meta-analysis was not appropriate. Conclusions Within the childhood and young adult population, TTD for cancer varies between diagnostic groups and with age at diagnosis in the majority of studies. In order that clear conclusions can be drawn from early diagnosis research in children and young adults, specific criteria identifying circumstances in which delay has occurred should accompany a defined time line to diagnosis or treatment in every study.

Outpatient and oral antibiotic management of low-risk febrile neutropenia are effective in children--a systematic review of prospective trials.

BackgroundThere is no consensus on whether therapeutic intensity can be reduced safely in children with low-risk febrile neutropenia (FN). Our primary objective was to determine whether there is a difference in efficacy between outpatient and inpatient management of children with low-risk FN. Our secondary objective was to compare oral and parenteral antibiotic therapy in this population.MethodsWe performed electronic searches of Ovid Medline, EMBASE, and the Cochrane Central Register of Controlled Trials, and limited studies to prospective pediatric trials in low-risk FN. Percentages were used as the effect measure.ResultsFrom 7,281 reviewed articles, 16 were included in the meta-analysis. Treatment failure, including antibiotic modification, was less likely to occur in the outpatient setting compared with the inpatient setting (15 % versus 28 %, P = 0.04) but was not significantly different between oral and parenteral antibiotic regimens (20 % versus 22 %, P = 0.68). Of the 953 episodes treated in the outpatient setting and 676 episodes treated with oral antibiotics, none were associated with infection-related mortality.ConclusionBased on the combination of results from all prospective studies to date, outpatient and oral antibiotic management of low-risk FN are effective in children and should be incorporated into clinical care where feasible.

An updated systematic review and meta-analysis of the predictive value of serum biomarkers in the assessment of fever during neutropenia in children with cancer.

Background: Fever during neutropenia (FN) is a frequent and potentially life-threatening complication of the treatment of childhood cancer. The role of biomarkers in predicting morbidity and mortality associated with FN in children has been explored with varying results. This systematic review identified, critically appraised and synthesized information on the use of biomarkers for the prediction of outcome of FN in children/young adults, updating a review of initial assessment and adding further analysis of their value at reassessment. Methods: This review was conducted in accordance with the Centre for Reviews and Dissemination Methods, using 3 different random effects meta-analysis models. Results: Thirty-seven studies involving over 4689 episodes of FN in children were assessed, including an additional 13 studies investigating 18 biomarkers in 1670 FN episodes since the original review. Meta-analysis was possible for admission C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 and interleukin-8 in their ability to detect significant infection. Marked heterogeneity exists, precluding clear clinical interpretation of the results. Qualitative synthesis of the role of serial biomarkers suggests their predictive ability may be more pronounced at 24 to 48 hours compared with admission. Direct comparisons of the discriminatory power of admission values of PCT and CRP showed PCT generally had a better discriminatory estimate of serious infection than CRP. Conclusions: There remains a paucity of robust and reproducible data on the use of biomarkers in prediction of serious infection in children with FN. Available evidence suggests PCT has better discriminatory ability than CRP and that the role of serial biomarkers warrants further study.

Prevention and management of neutropenic sepsis in patients with cancer: summary of NICE guidance

Neutropenic sepsis is a potentially fatal complication of treatment for cancer, with mortality rates of 2-21%.1 An investigation by the National Confidential Enquiry into Patient Outcome and Death and a follow-up report by the National Chemotherapy Advisory Group highlighted problems in the management of neutropenic sepsis in adults receiving chemotherapy.2 3 The problems included inadequate management of neutropenic sepsis leading to avoidable deaths, and the lack of systems for urgent assessment and of policies at organisation level for dealing with neutropenic sepsis. This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on the prevention and management of neutropenic sepsis in patients of any age with cancer.4 NICE recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Information and support for patients and carers ### Training for healthcare professionals ### Reducing the risk of septic complications of anticancer treatment

Time for paediatric febrile neutropenia guidelines – children are not little adults

L. Sung*, R. Phillips, T. Lehrnbecher Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 Program in Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8 Leeds Teaching Hospitals, NHS Trust, St. James’s University Hospital, Leeds, United Kingdom Department of Pediatrics, Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany

Guideline for the Management of Fever and Neutropenia in Children With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update

Purpose To update a clinical practice guideline (CPG) for the empirical management of fever and neutropenia (FN) in children with cancer and hematopoietic stem-cell transplantation recipients. Methods The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary and multinational group of experts in pediatric oncology and infectious diseases that includes a patient advocate. For questions of risk stratification and evaluation, we updated systematic reviews of observational studies. For questions of therapy, we conducted a systematic review of randomized trials of any intervention applied for the empirical management of pediatric FN. The Grading of Recommendation Assessment, Development and Evaluation approach was used to make strong or weak recommendations and to classify levels of evidence as high, moderate, low, or very low. Results Recommendations related to initial presentation, ongoing management, and empirical antifungal therapy of pediatric FN were reviewed; the most substantial changes were related to empirical antifungal therapy. Key differences from our 2012 FN CPG included the listing of a fourth-generation cephalosporin for empirical therapy in high-risk FN, refinement of risk stratification to define patients with high-risk invasive fungal disease (IFD), changes in recommended biomarkers and radiologic investigations for the evaluation of IFD in prolonged FN, and a weak recommendation to withhold empirical antifungal therapy in IFD low-risk patients with prolonged FN. Conclusion Changes to the updated FN CPG recommendations will likely influence the care of pediatric patients with cancer and those undergoing hematopoietic stem-cell transplantation. Future work should focus on closing research gaps and on identifying ways to facilitate implementation and adaptation.

A systematic review of models of care for the follow‐up of childhood cancer survivors

Follow‐up care for survivors of childhood cancer is increasingly seen as a priority service as numbers of survivors increase. Despite this there are few published evaluations of the available options. We conducted a systematic review of published and unpublished literature. Seven uncontrolled studies, and one comparative study of a related intervention, were identified. Observational data suggest that follow‐up care was useful even for patients who did not perceive this as a need. Suitably powered, well‐conducted, controlled trials of adequate duration that directly compare follow‐up models are required to provide robust evidence on the optimal care for these patients. Pediatr Blood Cancer 2013; 60: 351–356.