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

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

Parmsurv: a SAS Macro for Flexible Parametric Survival Analysis with Long-Term Predictions

Health economic evaluations often require predictions of survival rates beyond the follow-up period. Parametric survival models can be more convenient for economic modelling than the Cox model. The generalized gamma (GG) and generalized F (GF) distributions are extensive families that contain almost all commonly used distributions with various hazard shapes and arbitrary complexity. In this study, we present a new SAS macro for implementing a wide variety of flexible parametric models including the GG and GF distributions and their special cases, as well as the Gompertz distribution. Proper custom distributions are also supported. Different from existing SAS procedures, this macro not only supports regression on the location parameter but also on ancillary parameters, which greatly increases model flexibility. In addition, the SAS macro supports weighted regression, stratified regression and robust inference. This study demonstrates with several examples how the SAS macro can be used for flexible survival modeling and extrapolation.Comment: 15 pages, 1 figure, 10 tables, accepted by The Clinical Data Science Conference - PHUSE US Connect 202

Does a monetary incentive improve the response to a postal questionnaire in a randomised controlled trial? : the MINT incentive study

Background: Sending a monetary incentive with postal questionnaires has been found to improve the proportion of responders, in research in non-healthcare settings. However, there is little research on use of incentives to improve follow-up rates in clinical trials, and existing studies are inconclusive. We conducted a randomised trial among participants in the Managing Injuries of the Neck Trial (MINT) to investigate the effects on the proportion of questionnaires returned and overall non-response of sending a £5 gift voucher with a follow-up questionnaire. Methods: Participants in MINT were randomised to receive either: (a) a £5 gift voucher (incentive group) or (b) no gift voucher (no incentive group), with their 4 month or 8 month follow-up questionnaire. We recorded, for each group, the number of questionnaires returned, the number returned without any chasing from the study office, the overall number of non-responders (after all chasing efforts by the study office), and the costs of following up each group. Results: 2144 participants were randomised, 1070 to the incentive group and 1074 to the no incentive group. The proportion of questionnaires returned (RR 1.10 (95% CI 1.05, 1.16)) and the proportion returned without chasing (RR 1.14 (95% CI 1.05, 1.24) were higher in the incentive group, and the overall non-response rate was lower (RR 0.68 (95% CI 0.53, 0.87)). Adjustment for injury severity and hospital of recruitment to MINT made no difference to these results, and there were no differences in results between the 4-month and 8-month follow up questionnaires. Analysis of costs suggested a cost of £67.29 per additional questionnaire returned. Conclusion: Monetary incentives may be an effective way to increase the proportion of postal questionnaires returned and minimise loss to follow-up in clinical trials

Literature review of visual representation of the results of benefit–risk assessments of medicinal products

Background The PROTECT Benefit–Risk group is dedicated to research in methods for continuous benefit–risk monitoring of medicines, including the presentation of the results, with a particular emphasis on graphical methods. Methods A comprehensive review was performed to identify visuals used for medical risk and benefit–risk communication. The identified visual displays were grouped into visual types, and each visual type was appraised based on five criteria: intended audience, intended message, knowledge required to understand the visual, unintentional messages that may be derived from the visual and missing information that may be needed to understand the visual. Results Sixty-six examples of visual formats were identified from the literature and classified into 14 visual types. We found that there is not one single visual format that is consistently superior to others for the communication of benefit–risk information. In addition, we found that most of the drawbacks found in the visual formats could be considered general to visual communication, although some appear more relevant to specific formats and should be considered when creating visuals for different audiences depending on the exact message to be communicated. Conclusion We have arrived at recommendations for the use of visual displays for benefit–risk communication. The recommendation refers to the creation of visuals. We outline four criteria to determine audience–visual compatibility and consider these to be a key task in creating any visual. Next we propose specific visual formats of interest, to be explored further for their ability to address nine different types of benefit–risk analysis information

Recommendations for benefit–risk assessment methodologies and visual representations

Purpose The purpose of this study is to draw on the practical experience from the PROTECT BR case studies and make recommendations regarding the application of a number of methodologies and visual representations for benefit–risk assessment. Methods Eight case studies based on the benefit–risk balance of real medicines were used to test various methodologies that had been identified from the literature as having potential applications in benefit–risk assessment. Recommendations were drawn up based on the results of the case studies. Results A general pathway through the case studies was evident, with various classes of methodologies having roles to play at different stages. Descriptive and quantitative frameworks were widely used throughout to structure problems, with other methods such as metrics, estimation techniques and elicitation techniques providing ways to incorporate technical or numerical data from various sources. Similarly, tree diagrams and effects tables were universally adopted, with other visualisations available to suit specific methodologies or tasks as required. Every assessment was found to follow five broad stages: (i) Planning, (ii) Evidence gathering and data preparation, (iii) Analysis, (iv) Exploration and (v) Conclusion and dissemination. Conclusions Adopting formal, structured approaches to benefit–risk assessment was feasible in real-world problems and facilitated clear, transparent decision-making. Prior to this work, no extensive practical application and appraisal of methodologies had been conducted using real-world case examples, leaving users with limited knowledge of their usefulness in the real world. The practical guidance provided here takes us one step closer to a harmonised approach to benefit–risk assessment from multiple perspectives

Managing Injuries of the Neck Trial (MINT) : design of a randomised controlled trial of treatments for whiplash associated disorders

Background: A substantial proportion of patients with whiplash injuries develop chronic symptoms. However, the best treatment of acute injuries to prevent long-term problems is uncertain. A stepped care treatment pathway has been proposed, in which patients are given advice and education at their initial visit to the emergency department (ED), followed by review at three weeks and physiotherapy for those with persisting symptoms. MINT is a two-stage randomised controlled trial to evaluate two components of such a pathway: 1. use of The Whiplash Book versus usual advice when patients first attend the emergency department; 2. referral to physiotherapy versus reinforcement of advice for patients with continuing symptoms at three weeks. Methods: Evaluation of the Whiplash Book versus usual advice uses a cluster randomised design in emergency departments of eight NHS Trusts. Eligible patients are identified by clinicians in participating emergency departments and are sent a study questionnaire within a week of their ED attendance. Three thousand participants will be included. Patients with persisting symptoms three weeks after their ED attendance are eligible to join an individually randomised study of physiotherapy versus reinforcement of the advice given in ED. Six hundred participants will be randomised. Follow-up is at 4, 8 and 12 months after their ED attendance. Primary outcome is the Neck Disability Index (NDI), and secondary outcomes include quality of life and time to return to work and normal activities. An economic evaluation is being carried out. Conclusion: This paper describes the protocol and operational aspects of a complex intervention trial based in NHS emergency and physiotherapy departments, evaluating two components of a stepped-care approach to the treatment of whiplash injuries. The trial uses two randomisations, with the first stage being cluster randomised and the second individually randomised

Modelling Cognitive Decline in the Hypertension in the Very Elderly Trial [HYVET] and Proposed Risk Tables for Population Use

Although, on average, cognition declines with age, cognition in older adults is a dynamic process. Hypertension is associated with greater decline in cognition with age, but whether treatment of hypertension affects this is uncertain. Here, we modelled dynamics of cognition in relation to the treatment of hypertension, to see if treatment effects might better be discerned by a model that included baseline measures of cognition and consequent mortalityThis is a secondary analysis of the Hypertension in the Very Elderly Trial (HYVET), a double blind, placebo controlled trial of indapamide, with or without perindopril, in people aged 80+ years at enrollment. Cognitive states were defined in relation to errors on the Mini-Mental State Examination, with more errors signifying worse cognition. Change in cognitive state was evaluated using a dynamic model of cognitive transition. In the model, the probabilities of transitions between cognitive states is represented by a Poisson distribution, with the Poisson mean dependent on the baseline cognitive state. The dynamic model of cognitive transition was good (R(2) = 0.74) both for those on placebo and (0.86) for those on active treatment. The probability of maintaining cognitive function, based on baseline function, was slightly higher in the actively treated group (e.g., for those with the fewest baseline errors, the chance of staying in that state was 63% for those on treatment, compared with 60% for those on placebo). Outcomes at two and four years could be predicted based on the initial state and treatment.A dynamic model of cognition that allows all outcomes (cognitive worsening, stability improvement or death) to be categorized simultaneously detected small but consistent differences between treatment and control groups (in favour of treatment) amongst very elderly people treated for hypertension. The model showed good fit, and suggests that most change in cognition in very elderly people is small, and depends on their baseline state and on treatment. Additional work is needed to understand whether this modelling approach is well suited to the valuation of small effects, especially in the face of mortality differences between treatment groups.ClinicalTrials.gov NCT0012281

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

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.EThOS - Electronic Theses Online ServiceMHRA (GORMET study) and Innovative Medicines Initiative (PROTECT study)GBUnited Kingdo