Title: Bringing Innovative Methods for Early Phase Precision Medicine Trials Into Practice
Funder: Department of Health and Social Care

Abstract: Background: Phase I and Phase II clinical trials have a major impact on the later success of the development of the medicinal product. Therefore, early phase designs providing accurate conclusions are essential. The trial's accuracy is not, however, the only concern. There is also an ethical consideration: more patients in the trial should receive superior treatments to benefit the most. However, designs routinely applied to Phase I and Phase II trials often expose the majority of patients to suboptimal treatments. Response-adaptive designs can alter the allocation of patients throughout the trial towards better treatments. Response-adaptive designs that lead to greater patients' benefits while keeping the study's integrity have long been suggested for use in trials for the advantages they can offer. Nevertheless, their application is still sparse to date. The main reasons are thought to be unfamiliarity with novel methods and overlooked techniques to implement them given practical restrictions. Furthermore, many response-adaptive designs do not meet the needs of precision medicine by not allowing a personalised treatment selection, which is of interest in many novel trials, specifically, in basket, umbrella and platform trials. Aims and objectives: The aim of the project is to bridge response-adaptive designs for early phase clinical trials in precision medicine and real practice. The project consists of the implementation and methodological workstreams with the following objectives: 1. To facilitate the wider implementation of response-adaptive designs in early phase trials (Workstream 1). 2. To develop response-adaptive designs for Phase I dose-escalation trials (Workstream 2) and Phase II trials (Workstream 3) in precision medicine. Methods: The implementation objective will be achieved by: developing training courses/guidelines for CTUs; developing user-friendly software for planning and conducting of response-adaptive trials; developing efficient communication of such methods to patients/sponsors; supporting the implementation of response-adaptive trials in UK clinical trials. The methodological objective will be achieved by developing designs for personalised treatments; developing designs for trials with multiple endpoints; extending the methodology to basket, umbrella and platform trials. Timelines for delivery: The project is planned for five years with the implementation and methodological streams going in parallel, and the objectives evenly distributed over the period. The training courses for CTUs and outreach visits are planned to take place regularly during the project. Anticipated impact and dissemination: The project will make response-adaptive methods a more viable option for early phase trials and will facilitate their wider applications in studies conducted by CTUs. This will increase the number of patients receiving superior treatments in trials and will reduce the risk of under-recruitment by making participation more appealing. The project is also expected to influence other methodological works on response-adaptive designs by bringing attention to the practical aspects. The principal outlets for dissemination of the project will be (i) regular outreach visits to CTUs across the UK promoting response-adaptive designs and providing training to trialists on their implementation, (ii) a series of online videos aimed at patients and general public on the benefits of response-adaptive designs, and (iii) publications in high-impact trials and statistical journals.

Lay abstract: Background Before a medicine is approved for use, it has to undergo clinical trials to test whether it is safe and has a positive effect on patients' health. This evaluation is a lengthy and expensive process, yet, many developments fail late in the process having exposed participants to ineffective/harmful treatments while costing substantial amounts of money. One of the reasons for these failures is inaccurate decisions made at early stages of developments. A key to reducing the risks of such decisions are quantitative, statistical approaches. Appropriate use of statistical methods allows the clinical researcher to make reliable decisions in the presence of uncertainty. Motivation Making the right decisions about new medicines is not the only concern. It is also important that the patients participating in clinical trials could gain significant benefit for them. Novel statistical methods known as outcome-adjusted (or response-adaptive) methods can help to achieve this aim. As a clinical trial progresses, these methods can identify which medicines lead a better patient response and can recommend them for future patients in the trial. As a result, patients are more likely to receive better medicine. Unfortunately, there is no such thing as a free lunch. Approaches that focus on improving the patients' benefits in the trial are more complex to implement than many statistical methods currently used. The logistical preparations for the trial are more involved and extra training is required for all parties involved in clinical trials: patients, clinicians, trialists. As a result, such methods have remained theoretical exercises rather than a way to make clinical trials more ethical and beneficial for patients. Additionally, there are many factors that can affect a patient's response to medicine, e.g. age, weight, previous treatments, etc. Taking these into account can lead to more personalised therapies and improve patients' benefits. However, currently, there are very few methods that consider these factors in the early stages of developments. Aims of the research This proposal has two aims: to bridge the existing gap between advanced statistical methods and the current UK clinical trial practice; and to develop methods for more personalised treatment; Methods These aims will be achieved by identifying the common drivers and hurdles for patients to take part in outcome-adjusted trials; identifying the obstacles faced by UK clinical trial units in using outcome-adjusted methods; developing statistical methods for these needs; providing training for patients, clinicians and applied researchers in clinical trial units. These steps will be the means to the final and most important step which is to support the implementation of a novel outcome-adjusted method in at least one UK clinical trial. This trial will serve as an example to the UK clinical trial units on how methods that improve patients' benefits can be put into practice. The goals will be achieved by working closely with patients' representatives and practising clinicians. Joint work will ensure that the research meets the patients' needs. Dissemination Reviews of advantages and the common challenges in implementing outcome-adjusted methods will be made freely available online to raise awareness amongst researchers. The novel statistical methods will be published in leading journals. The training materials will be also available online along with user-friendly software to help clinical trial units to implement the newly developed statistical methods. Results will be also disseminated beyond clinical and statistical communities, to patients and the general public. An awareness of outcome-adjusted methods will be increased by a series of popular-science videos focusing on their advantages and challenges. The progress of the project will be regularly reported through the videos increasing an understanding of how the undertaken research affects patients' lives.

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