Title: Adaptive Design Clinical Trials and their Impact on the Economic Evaluation of Health Care Technologies
Funder: Department of Health and Social Care

Abstract: Background: It is important to evaluate new health technologies efficiently. Decision makers such as National Institute for Health and Care Excellence (NICE) require high quality evidence of both the clinical and cost-effectiveness of a technology when making funding recommendations. Adaptive designs can facilitate efficient clinical trial designs to provide this information.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) Adaptive designs use data collected as the trial progresses to inform modifications to the trial. They directly benefit patients and the NHS ethically and financially. However, there can be issues if only clinical effectiveness is used in adaptive design decision making. It is possible that resources are wasted if a trial ends with insufficient evidence to show cost-effectiveness, a trial continues unnecessarily when there is early evidence the technology is not cost-effective or incorrect decisions are made as cost-effectiveness is only shown because of bias introduced into the assessment. CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) An identified lack of familiarity of adaptive designs amongst health economists may mean these limitations are not fully considered, potentially undermining the benefits of adaptive designs to patients. Enhancing the knowledge and utilising the expertise of health economists in the design and analysis of adaptive trials is vital.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) Aims: This fellowship aims to answer the question Can adaptive designs be used to assess the cost-effectiveness of new health technologies? The project will evaluate the impact of using data from adaptive designs to inform health economic evaluations.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) Patients and the NHS will benefit as methods to assess the cost-effectiveness of health technologies through adaptive study designs are evaluated and recommendations made for the best approaches for accurate decision making.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) Plan of investigation: This fellowship has a methodological focus with existing methods for the analysis of adaptive designs, health economic analysis and value of information (VOI) analysis applied in an innovative way. CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) The fellowship will extensively review the literature on current methods for economic evaluation and VOI analysis in adaptive designs. The limitations of adaptive designs and associated methodology will be identified and their potential impact on health economics evaluated. It is anticipated that methodology exists to overcome some limitations but the methods are yet to be applied in the health economics context. Interviews with health economic experts, decision makers and patients will identify practical and ethical limitations of adaptive designs.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) Different approaches to analysing health economic outcomes in adaptive designs will be considered, utilising the findings of the literature searches and interviews. The two approaches are: Clinical and cost-effectiveness analyses conducted in sequence. Health economic analysis is carried out once an adaptive trial has terminated. Adaptive study decisions are made based only on clinical effectiveness. The impact of the limitations of adaptive designs on the health economic analysis will be evaluated;CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) Clinical and cost-effectiveness analyses conducted in parallel. An interim analysis provides an opportunity to carry out health economic and VOI analyses. Adaptive study decisions are made based on cost as well as clinical effectiveness. The impact of the adaptive study design on these analyses will be explored. Both modelling and alongside the trial approaches to economic evaluation will be explored.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) Utilising the world leading Emergency Medicine Research in Sheffield (EMRiS) and building on my current research on the use of adaptive designs in emergency medicine trials, case studies will be drawn from the emergency medicine setting. Fixed trials to be re-analysed as if they were adaptive include 3Mg and RATPAC.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) Guidelines will be produced recommending adjustments to the analysis of health economic outcomes of an adaptive design. The utility, practicality and ethics of incorporating health economics into the design of an adaptive trial will be discussed. Recommendations will be generalised beyond emergency medicine using further case studies.

Lay abstract: What will this research find out? This research aims to establish whether using adaptive designs can impact our ability to assess clinical and cost-effectiveness.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) What are clinical and cost-effectiveness? In the UK there are many treatments available to treat a wide range of illnesses. Limited budgets mean the NHS cannot pay for them all. Decisions must be made based on evidence that a treatment works - clinical effectiveness - and whether it is deemed to be value for money - cost-effectiveness.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) The National Institute of Health and Care Excellence (NICE) are responsible for making decisions about which treatments to fund. They require high quality evidence of a treatment's clinical and cost-effectiveness.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) What is an adaptive design? To show a new treatment works we often conduct a clinical trial. Before the trial begins we use statistics to decide how many people are needed and how long the trial will run for. We also specify the statistical methods we plan to use to show the treatment is clinically effective. Usually, once the trial has begun we do not look at these data until the trial has ended.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) An alternative is to use an adaptive design. This allows us to examine the data before the trial has ended. Based on what we see, we can make changes to the way the rest of the trial is conducted. One possibility is to stop the trial earlier than planned because enough data has been collected to show a treatment works.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) Adaptive designs have the potential to save patients, time and money. For example, at an early look at the data collected from an adaptive trial we can see the new treatment is working much better than the old. This means we can stop the trial 6 months earlier than planned and patients receive the better treatment much sooner. We also save the time and money we would have spent had we carried on. Patients benefit from more research for the same cost.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) Why is this research important? When setting up an adaptive trial and looking at the data, the changes made are often motivated by showing a treatment works. Despite its importance, showing the treatment is value for money is not a priority. By focusing on clinical effectiveness we may end up with less information to show cost-effectiveness.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) The clear benefits to patients of adaptive designs have made them more popular. We know very little, however, about their impact on the accurate calculation of cost-effectiveness. It is possible treatments are funded based on clinical effectiveness and not whether they are value for money. This could mean patients are unable to receive the treatment they need as the NHS is wasting money on costly alternatives.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) How will this research be carried out? I will conduct a review of published research to see how researchers currently calculate cost-effectiveness in adaptive and non-adaptive trials. I will identify how using adaptive designs might impact on the calculation of value for money. This will include any practical and ethical issues. CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) I will then consider two approaches to analysing cost-effectiveness when an adaptive clinical trial is used: Calculating the clinical effectiveness of a treatment is prioritised. The estimation of a treatment's cost-effectiveness is only calculated once the adaptive trial has ended.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) Calculating the cost-effectiveness of a treatment is given equal priority to clinical effectiveness. Early looks at the data are used to inform changes to the trial based on both clinical and cost-effectiveness.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) How will patients and the public be involved? This research is likely to raise a number of important ethical issues. The two methods proposed have different views on the importance of cost-effectiveness in a clinical trial. The first prioritises the evaluation of clinical effectiveness and the second considers both clinical and cost-effectiveness equally. It is anticipated that patients and the public will have differing views about the importance of costs in decision making. Interviews will be conducted to establish these views and also assess any potential risks and benefits to patients of this research. Any issues raised will be addressed in the ongoing research.CHAR(13) + CHAR(10)CHAR(13) + CHAR(10) What will happen with the findings? This research will provide recommendations to researchers to ensure accurate estimation of cost-effectiveness when an adaptive design is used. Decision makers will then have accurate information when deciding which treatments to fund. This will make sure patients have access to treatments that provide the maximum improvements in health for the money available and the benefits to patients of adaptive designs are not undermined.

Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE