Title: Investigating the Impact of Adjudication in Stroke Trials
Funder: Department of Health and Social Care

Abstract: Background: Adjudication in clinical trials refers to verification of diagnosis, outcome or safety data by one or more independent experts. It has become convention to include adjudication in trials investigating cardiovascular diseases such as stroke, in spite of a lack of proven benefit. Adjudication can help to improve accurate classification of events and control differential misclassification. However, researchers have started to question the need for adjudication. Adjudication is a costly procedure and can result in a significant delay in a clinical trial. Few studies have investigated how adjudication impacts on stroke outcomes. Aims: In three linked Work Packages (WP), this programme will aim to address the following question: What are the benefits and costs of adjudicating outcomes in stroke trials? Plan of Investigation: Stroke trials will be defined as randomised controlled trials where the primary outcome is either occurrence of stroke, type of stroke, or functional outcome after stroke. Outcomes investigated will be the primary outcome of stroke trials and some secondary outcomes, including adverse outcomes such as bleeding. WP1: Systematic review and meta-analyses evaluating the impact of adjudication in Stroke Trials Aim: To assess the effects of adjudicator-assessed outcomes versus site-assessed outcomes on the treatment effect estimates for stroke trials This review will give evidence to assess the role of adjudication in stroke trials. All stroke trials where the primary outcome is adjudicated will be located, assessed for eligibility and pooled if suitable. The impact of adjudication will be assessed by calculating the ratio of treatment effects for each trial, as the treatment estimate using site-assessed outcomes versus the treatment estimate using adjudicator-assessed outcomes. WP2: Cost-effectiveness analysis of adjudication in stroke trials Aim: To investigate the cost-effectiveness of adjudication in stroke trialsThis analysis will examine a series of case studies to estimate the cost of the adjudication process in comparison with the impact on correct assessment of outcomes. These case studies will be obtained from data received from studies identified in WP1 and data held at the Nottingham Stroke Trials Unit. Cost-effectiveness ratios will be calculated and decision tree modelling will be used to investigate the expected value of adjudication for various plausible situations.WP3: Statistical simulation modelling the effect of adjudication on bias and precision of unadjudicated outcomesAim: To investigate how adjudication impacts on the bias and precision of unadjudicated outcomes and how this affects the sample size needed for a trial Statistical simulations based on real trial data will be created. These will explore the impact of adjudication on bias and precision of estimated treatment effects derived from unadjudicated outcomes. Non-differential and differential misclassification will be introduced to understand how this affects the estimates. The relation between bias, precision and sample size will be investigated. Benefits to patients and the NHS: This research will provide evidence to understand the process of adjudication. If it is found that adjudication is not needed in some situations, the unnecessary inclusion of adjudication for some studies will be reduced. The trials which do not include adjudication will be more efficient, ensuring greater potential funding for other research. Quicker trials and more research funding will directly filter down to patients who will benefit from the development of new interventions and improved care. In some trial settings, adjudication may be found to be vital. Where adjudication is necessary in ensuring unbiased and precise results, the inclusion of the adjudication process will improve the quality of trial conclusions. This will result in trials providing valid answers to clinical questions, resulting in a high quality pool of evidence for clinicians to exploit when making decisions about patients' care and wellbeing.

Lay abstract: What is adjudication? Adjudication in clinical trials means the review of trial data by independent experts in order to confirm outcomes, such as diagnoses, safety findings or endpoints. For example, in stroke trials experts may assess if a participant has had a stroke (diagnoses), how much bleeding there was in the brain (safety findings) or how a participant functions 90 days after a stroke (endpoints). Adjudication works by helping to review outcomes in a clinical trial. For example, in trials where the main outcome is if participants have a stroke, doctors will look at brain scans and give a diagnosis of stroke or non-stroke. In a trial including adjudication, these brain scans are then sent to doctors who have no other involvement in the trial, called adjudicators, for them to also decide if the participant has had a stroke. The two diagnoses are compared and a final decision is made about if the participant has had a stroke. There is not enough evidence to decide if including adjudication in trials is useful. Positives and negatives of adjudication: At the moment, adjudication is often included in stroke trials as it is thought that having an independent opinion about patient outcomes makes the trial stronger. It should reduce any bias, pick up errors and the results should be more accurate. However, since stroke trials often have many hundreds of participants, adjudication can be expensive and time consuming. For example, adjudication alone cost over 500,000 for one trial. Adjudicators do not usually see the patients but review scans, videos and other information from patient medical records to make their decisions. Because of this, some researchers think that the decisions of the adjudicators are not always better than those of doctors, who spend time with the patients before making a judgement. Researchers have now started to question the need for adjudication. Some stroke trials have shown that adjudication is useful, but other stroke trials have also found that adjudication is not needed. A review of 10 stroke and heart attack clinical trials in 2009 showed that the results of the trials would have been similar if there had been no adjudication. More work is needed to look into this. Research Plan: This research will aim to answer the question: What are the benefits and costs of adjudicating outcomes in stroke trials? It will do this in three ways: 1. A review of the literature of stroke trials that have used adjudication will examine if not having adjudication would have changed the results. This review will find out in which situations it is useful to include adjudication and in which situations it isn't. 2. The cost of adjudication will be evaluated. These costs will be compared to the benefits it has brought to the trial. This will find out for what kind of trials adjudication is most cost-effective. 3. A Statistical method, called simulation, will use data from previous stroke trials to see how adjudication affects the precision of results and the conclusions made. Benefit of this research to patients and the NHS: This research will help to understand the need for adjudication in stroke trials. If it is found that adjudication is not needed in some situations, then these trials could stop using adjudicators, which should result in quicker, more efficient studies. The trials which do not include adjudication will cost less, so there will be more money available for other research. Quicker trials and more research funding will benefit patients with the development of new treatments and improved care. If, for some situations adjudication is found to be important, then making sure there is adjudication in these trials will make them high quality. This will ensure that trial results are correct and the conclusions are valid. Therefore, the research questions asked by these trials will be properly answered. This will mean doctors can use high quality evidence to decide about the best treatment for their patients. Using the findings of this research: These findings can be used directly after the fellowship has finished. Stroke researchers can use the results when they design their next stroke trial. Also, some of these findings may be used in other areas apart from stroke. This is because there are strong similarities between adjudication in stroke trials and adjudication in other studies, such as heart attack trials.

Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: STROKE