How can health economics be used in the design and analysis of adaptive clinical trials? A qualitative analysis

Introduction Adaptive designs offer a flexible approach, allowing changes to a trial based on examinations of the data as it progresses. Adaptive clinical trials are becoming a popular choice, as the prudent use of finite research budgets and accurate decision-making are priorities for healthcare providers around the world. The methods of health economics, which aim to maximise the health gained for money spent, could be incorporated into the design and analysis of adaptive clinical trials to make them more efficient. We aimed to understand the perspectives of stakeholders in health technology assessments to inform recommendations for the use of health economics in adaptive clinical trials. Methods A qualitative study explored the attitudes of key stakeholders—including researchers, decision-makers and members of the public—towards the use of health economics in the design and analysis of adaptive clinical trials. Data were collected using interviews and focus groups (29 participants). A framework analysis was used to identify themes in the transcripts. Results It was considered that answering the clinical research question should be the priority in a clinical trial, notwithstanding the importance of cost-effectiveness for decision-making. Concerns raised by participants included handling the volatile nature of cost data at interim analyses; implementing this approach in global trials; resourcing adaptive trials which are designed and adapted based on health economic outcomes; and training stakeholders in these methods so that they can be implemented and appropriately interpreted. Conclusion The use of health economics in the design and analysis of adaptive clinical trials has the potential to increase the efficiency of health technology assessments worldwide. Recommendations are made concerning the development of methods allowing the use of health economics in adaptive clinical trials, and suggestions are given to facilitate their implementation in practice

Assurance Methods for designing a clinical trial with a delayed treatment effect

An assurance calculation is a Bayesian alternative to a power calculation. One may be performed to aid the planning of a clinical trial, specifically setting the sample size or to support decisions about whether or not to perform a study. Immuno-oncology (IO) is a rapidly evolving area in the development of anticancer drugs. A common phenomenon that arises from IO trials is one of delayed treatment effects, that is, there is a delay in the separation of the survival curves. To calculate assurance for a trial in which a delayed treatment effect is likely to be present, uncertainty about key parameters needs to be considered. If uncertainty is not considered, then the number of patients recruited may not be enough to ensure we have adequate statistical power to detect a clinically relevant treatment effect. We present a new elicitation technique for when a delayed treatment effect is likely to be present and show how to compute assurance using these elicited prior distributions. We provide an example to illustrate how this could be used in practice. Open-source software is provided for implementing our methods. Our methodology makes the benefits of assurance methods available for the planning of IO trials (and others where a delayed treatment expect is likely to occur)

Preventing and lessening exacerbations of asthma in school-age children associated with a new term (PLEASANT) : Study protocol for a cluster randomised control trial

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedBackground: Within the UK, during September, there is a pronounced increase in the number of unscheduled medical contacts by school-aged children (4-16 years) with asthma. It is thought that that this might be caused by the return back to school after the summer holidays, suddenly mixing with other children again and picking up viruses which could affect their asthma. There is also a drop in the number of prescriptions administered in August. It is possible therefore that children might not be taking their medication as they should during the summer contributing to them becoming ill when they return to school. It is hoped that a simple intervention from the GP to parents of children with asthma at the start of the summer holiday period, highlighting the importance of maintaining asthma medication can help prevent increased asthma exacerbation, and unscheduled NHS appointments, following return to school in September.Methods/design: PLEASANT is a cluster randomised trial. A total of 140 General Practices (GPs) will be recruited into the trial; 70 GPs randomised to the intervention and 70 control practices of "usual care" An average practice is expected to have approximately 100 children (aged 4-16 with a diagnosis of asthma) hence observational data will be collected on around 14000 children over a 24-month period. The Clinical Practice Research Datalink will collect all data required for the study which includes diagnostic, prescription and referral data.Discussion: The trial will assess whether the intervention can reduce exacerbation of asthma and unscheduled medical contacts in school-aged children associated with the return to school after the summer holidays. It has the potential to benefit the health and quality of life of children with asthma while also improving the effectiveness of NHS services by reducing NHS use in one of the busiest months of the year. An exploratory health economic analysis will gauge any cost saving associated with the intervention and subsequent impacts on quality of life. If results for the intervention are positive it is hoped that this could be adopted as part of routine care management of childhood asthma in general practice. Trial registration: Current controlled trials: ISRCTN03000938 (assigned 19/10/12) http://www.controlled-trials.com/ISRCTN03000938/.UKCRN ID: 13572.Peer reviewe

A review of clinical trials with an adaptive design and health economic analysis

An adaptive design uses data collected as a clinical trial progresses to inform modifications to the trial. Hence, adaptive designs and health economics aim to facilitate efficient and accurate decision-making. However, it is unclear whether the methods are considered together in the design, analysis and reporting of trials. This review aims to establish how health economic outcomes are utilised in the design, analysis and reporting of adaptive designs. Registered and published trials up to August 2016 with an adaptive design and health economic analysis were identified. The use of health economics in the design, analysis and reporting was assessed. Summary statistics are presented and recommendations formed based on the research team’s experiences and a practical interpretation of the results. Thirty-seven trials with an adaptive design and health economic analysis were identified. It was not clear whether the health economic analysis accounted for the adaptive design in 17/37 trials where this was thought necessary, nor whether health economic outcomes were utilised at the interim analysis for 18/19 of trials with results. The reporting of health economic results was sub-optimal for the (17/19) trials with published results. Appropriate consideration is rarely given to the health economic analysis of adaptive designs. Opportunities to utilise health economic outcomes in the design and analysis of adaptive trials are being missed. Further work is needed to establish whether adaptive designs and health economic analyses can be used together to increase the efficiency of health technology assessments without compromising accuracy

Appropriate design and reporting of superiority, equivalence and non-inferiority clinical trials incorporating a benefit risk assessment: the BRAINS study including expert workshop

Background Randomised controlled trials are designed to assess the superiority, equivalence or non-inferiority of a new health technology, but which trial design should be used is not always obvious in practice. In particular, when using equivalence or non-inferiority designs, multiple outcomes of interest may be important for the success of a trial, despite the fact that usually only a single primary outcome is used to design the trial. Benefit–risk methods are used in the regulatory clinical trial setting to assess multiple outcomes and consider the trade-off of the benefits against the risks, but are not regularly implemented in publicly funded trials. Objectives The aim of the project is to aid the design of clinical trials with multiple outcomes of interest by defining when each trial design is appropriate to use and identifying when to use benefit–risk methods to assess outcome trade-offs (qualitatively or quantitatively) in a publicly funded trial setting. Methods A range of methods was used to elicit expert opinion to answer the project objectives, including a web-based survey of relevant researchers, a rapid review of current literature and a 2-day consensus workshop of experts (in 2019). Results We created a list of 19 factors to aid researchers in selecting the most appropriate trial design, containing the following overarching sections: population, intervention, comparator, outcomes, feasibility and perspectives. Six key reasons that indicate a benefit–risk method should be considered within a trial were identified: (1) when the success of the trial depends on more than one outcome; (2) when important outcomes within the trial are in competing directions (i.e. a health technology is better for one outcome, but worse for another); (3) to allow patient preferences to be included and directly influence trial results; (4) to provide transparency on subjective recommendations from a trial; (5) to provide consistency in the approach to presenting results from a trial; and (6) to synthesise multiple outcomes into a single metric. Further information was provided to support the use of benefit–risk methods in appropriate circumstances, including the following: methods identified from the review were collated into different groupings and described to aid the selection of a method; potential implementation of methods throughout the trial process were provided and discussed (with examples); and general considerations were described for those using benefit–risk methods. Finally, a checklist of five pieces of information that should be present when reporting benefit–risk methods was defined, with two additional items specifically for reporting the results. Conclusions These recommendations will assist research teams in selecting which trial design to use and deciding whether or not a benefit–risk method could be included to ensure research questions are answered appropriately. Additional information is provided to support consistent use and clear reporting of benefit–risk methods in the future. The recommendations can also be used by funding committees to confirm that appropriate considerations of the trial design have been made. Limitations This research was limited in scope and should be considered in conjunction with other trial design methodologies to assess appropriateness. In addition, further research is needed to provide concrete information about which benefit–risk methods are best to use in publicly funded trials, along with recommendations that are specific to each method

Preventing and Lessening Exacerbations of Asthma in School-aged children Associated with a New Term (PLEASANT): recruiting primary care research sites - the PLEASANT experience

Background: Recruitment of general practices and their patients into research studies is frequently reported as a challenge. The Preventing and Lessening Exacerbations of Asthma in School-aged children Associated with a New Term (PLEASANT) trial recruited 142 general practices, across England and Wales and delivered the study intervention to time and target. Aims: To describe the process of recruitment used within the cluster randomised PLEASANT trial and present results on factors that influenced recruitment. Methods: Data were collected on the number of and types of contact used to gain expression of interest and subsequent randomisation into the PLEASANT trial. Practice size and previous research experience were also collected. Results: The mean number of contacts required to gain expression of interest were m=3.01 (s.d. 1.6) and total number of contacts from initial invitation to randomisation m=6.8 (s.d. 3.5). Previous randomised controlled trial involvement (hazard ratio (HR)=1.81 (confidence interval (CI) 95%, 1.55–2.11) P<0.001) and number of studies a practice had previously engaged in (odds ratio (OR) 1.91 (CI 95%, (1.52–2.42)) P<0.001), significantly influenced whether a practice would participate in PLEASANT. Practice size was not a significant deciding factor (OR=1.04 (95% CI 0.99–1.08) P=0.137). Conclusions: Recruitment to time and target can be achieved in general practice. The amount of resource required for site recruitment should not, however, be underestimated and multiple strategies for contacting practices should be considered. General practitioners with more research experience are more likely to participate in studies

Progression criteria in trials with an internal pilot : an audit of publicly funded randomised controlled trials

Background With millions of pounds spent annually on medical research in the UK, it is important that studies are spending funds wisely. Internal pilots offer the chance to stop a trial early if it becomes apparent that the study will not be able to recruit enough patients to show whether an intervention is clinically effective. This study aims to assess the use of internal pilots in individually randomised controlled trials funded by the Health Technology Assessment (HTA) programme and to summarise the progression criteria chosen in these trials. Methods Studies were identified from reports of the HTA committees’ funding decisions from 2012 to 2016. In total, 242 trials were identified of which 134 were eligible to be included in the audit. Protocols for the eligible studies were located on the NIHR Journals website, and if protocols were not available online then study managers were contacted to provide information. Results Over two-thirds (72.4%) of studies said in their protocol that they would include an internal pilot phase for their study and 37.8% of studies without an internal pilot had done an external pilot study to assess the feasibility of the full study. A typical study with an internal pilot has a target sample size of 510 over 24 months and aims to recruit one-fifth of their total target sample size within the first one-third of their recruitment time. There has been an increase in studies adopting a three-tiered structure for their progression rules in recent years, with 61.5% (16/26) of studies using the system in 2016 compared to just 11.8% (2/17) in 2015. There was also a rise in the number of studies giving a target recruitment rate in their progression criteria: 42.3% (11/26) in 2016 compared to 35.3% (6/17) in 2015. Conclusions Progression criteria for an internal pilot are usually well specified but targets vary widely. For the actual criteria, red/amber/green systems have increased in popularity in recent years. Trials should justify the targets they have set, especially where targets are low

A theory-based online health behaviour intervention for new university students (U@Uni): results from a randomised controlled trial

BACKGROUND Too few young people engage in behaviours that reduce the risk of morbidity and premature mortality, such as eating healthily, being physically active, drinking sensibly and not smoking. This study sought to assess the efficacy and cost-effectiveness of a theory-based online health behaviour intervention (based on self-affirmation theory, the Theory of Planned Behaviour and implementation intentions) targeting these behaviours in new university students, in comparison to a measurement-only control. METHODS Two-weeks before starting university all incoming undergraduates at the University of Sheffield were invited to take part in a study of new students' health behaviour. A randomised controlled design, with a baseline questionnaire, and two follow-ups (1 and 6 months after starting university), was used to evaluate the intervention. Primary outcomes were measures of the four health behaviours targeted by the intervention at 6-month follow-up, i.e., portions of fruit and vegetables, metabolic equivalent of tasks (physical activity), units of alcohol, and smoking status. RESULTS The study recruited 1,445 students (intervention n = 736, control n = 709, 58% female, Mean age = 18.9 years), of whom 1,107 completed at least one follow-up (23% attrition). The intervention had a statistically significant effect on one primary outcome, smoking status at 6-month follow-up, with fewer smokers in the intervention arm (8.7%) than in the control arm (13.0%; Odds ratio = 1.92, p = .010). There were no significant intervention effects on the other primary outcomes (physical activity, alcohol or fruit and vegetable consumption) at 6-month follow-up. CONCLUSIONS The results of the RCT indicate that the online health behaviour intervention reduced smoking rates, but it had little effect on fruit and vegetable intake, physical activity or alcohol consumption, during the first six months at university. However, engagement with the intervention was low. Further research is needed before strong conclusions can be made regarding the likely effectiveness of the intervention to promote health lifestyle habits in new university students. TRIAL REGISTRATION Current Controlled Trials, ISRCTN67684181

Conservative management versus open reduction and internal fixation for mid-shaft clavicle fractures in adults - The Clavicle Trial: Study protocol for a multicentre randomized controlled trial

Background: Clavicle fractures account for around 4% of all fractures and up to 44% of fractures of the shoulder girdle. Fractures of the middle third (or mid-shaft) account for approximately 80% of all clavicle fractures. Management of this group of fractures is often challenging and the outcome can be unsatisfactory. In particular it is not clear whether surgery produces better outcomes than non-surgical management. Currently there is much variation in the use of surgery and a lack of good quality evidence to inform our decision.Methods/Design: We aim to undertake a multicentre randomised controlled trial evaluating the effectiveness and safety of conservative management versus open reduction and internal fixation for displaced mid-shaft clavicle fractures in adults. Surgical treatment will be performed using the Acumed clavicle fixation system. Conservative management will consist of immobilisation in a sling at the side in internal rotation for 6 weeks or until clinical or radiological union. We aim to recruit 300 patients. These patients will be followed-up for at least 9 months. The primary endpoint will be the rate of non-union at 3 months following treatment. Secondary endpoints will be limb function measured using the Constant-Murley Score and the Disabilities of the Arm, Shoulder and Hand (DASH) Score at 3 and 9 months post-operatively.Discussion: This article presents the protocol for a multicentre randomised controlled trial. It gives extensive details of, and the basis for, the chosen methods, and describes the key measures taken to avoid bias and to ensure validity.Trial Registration: United Kingdom Clinical Research Network ID: 8665. The date of registration of the trial is 07/09/2006. The date the first patient was recruited is 18/12/2007. © 2011 Longo et al; licensee BioMed Central Ltd