Improving evidence-based risk-benefit decision-making of medicines for children

Abstract

Risk-benefit assessment for decision-making based on evidence is a subject of continuing interest. However, randomised clinical trials evidence of risks and benefits are not always available especially for drugs used in children mainly due to ethical concern of children being subjects of clinical trials. This thesis appraises risk-benefit evidence from published trials in children for the case study; assesses the risk-benefit balance of drugs, proposes a framework for risk-benefit evidence synthesis, and demonstrates the extent of its contribution. The review shows trial designs lack safety planning leading to inconsistency safety reporting, and lack of efficacy evidence. The General Practice Research Database (GPRD) data was exploited to synthesise evidence of risks of cisapride and domperidone in children with gastro-oesophageal reflux as a case study. Efficacy data are only available through review evidence. Analysis of prescribing trends does not identify further risk-benefit issues but suggest the lack of evidence has led to inappropriate prescribing in children. Known adverse events are defined from the British National Formulary and quantified. Proportional reporting ratio technique is applied to other clinical events to generate potential safety signals. Signals are validated; and analysed for confirmatory association through covariates adjustment in regressions. The degree of associations between signals and drugs are assessed using Bradford Hill’s criteria for causation. Verified risks are known adverse events with 95% statistical significance, and signals in abdominal pain group and bronchitis and bronchiolitis group. The drugs’ risk-benefit profiles are illustrated using the two verified signals and an efficacy outcome. Sensitivity of input parameters is studied via simulations. The findings are used to hypothetically advise risk-benefit aspects of trial designs. The value of information from this study varies between stakeholders and the keys to communicating risks and benefits lie in presentation and understanding. The generalisability and scope of the proposed methods are discussed