Title: The analysis of overall survival in a changing clinical world; the methodological implications of relapsing cancers in randomised controlled trials.
Funder: Department of Health and Social Care

Abstract: Background The assessment of overall survival, as a primary or secondary endpoint, is an important result from a phase III clinical trial. It is used to determine the clinical and cost effectiveness of the experimental intervention compared to the control intervention. However, in the context of relapsing cancers, this assessment can be confounded when trial participants receive additional lines of anti-cancer therapy post-trial. Recent developments in methodology have begun to account for this confounding in the case of treatment switching. Treatment switching occurs when patients in the control arm receive the experimental intervention post-trial. This can often occur by design but may also be the result of an evolving clinical landscape. However, treatment switching does not incorporate all possibilities and is only applicable in some cases. Therefore, there is a need for methodology to be developed or extended which addresses the problem as a whole. Aim To develop new or extend existing methodology which assesses overall survival whilst accounting for subsequent lines of anti-cancer therapy. Objectives To determine how overall survival is currently being analysed in the presence of subsequent anti-cancer therapy, identify the key issues with the current approaches and what the main research priorities are according to all stakeholders. To build on existing methods or develop new methodology to address the main priorities as identified by stakeholders. To assess the developed method by comparing it to existing methods in a simulation study and recent clinical trial data. To ensure that the developed method is available and accessible to all stakeholders.Methods A stakeholder consultation will be held to identify the main priorities regarding the analysis of overall survival according to patients, the public, statisticians, clinicians and health care payers. Consensus will be sought using a Delphi exercise. A targeted literature review will consider whether a method can be developed or extended to address the main priorities identified from the stakeholder consultation using one or a combination of the methodologies applied in: Other relapsing conditions, e.g. depression or alcoholism Treatment switching (causal inference) Recurrent event analysisThe new methodology will be tested within a simulation study and compared to existing methods in simulated and real data. Once tested it will be made accessible through workshops and open source statistical software. The availability of the data required to use the new and existing methods will be explored along with the requirements on how to access routine data sources. Impact The collaborative nature of this work will ensure that the developed methodology is relevant and accessible to all stakeholders. Publications and presentations aimed at statistical and non-statistical audiences will be written to explain the results and facilitate uptake. Once applied, the proposed method will provide a more reliable assessment of overall survival in the context of relapsing cancers. This will facilitate healthcare payers making well-informed decisions on whether a new intervention should be made available on the NHS. Improved evidence and resource allocation decisions will consequently enable patients to receive the best possible care.

Lay abstract: Within cancer research we use 'overall survival' as a way to evaluate new treatments. It is the length of time, from the date of diagnosis or the start of treatment that a patient with a serious disease or condition is alive. Overall survival is also important evidence in support of a cancer treatment being made available to NHS patients. However, not all cancers can be controlled with one type or 'line' of treatment. After a period of controlling the disease, the cancer may start to grow again (progress) and a new line of treatment is needed. A clinical trial investigates whether a new treatment works in a well-defined setting. Patients taking part in the trial, known as participants, will either receive the new (experimental) treatment or the current standard (control) treatment. In a clinical trial, overall survival is measured from the point participants are assigned their trial treatment. However, if the cancer progresses, participants will usually stop their trial treatment and may start a different treatment. This different treatment is no longer determined by the clinical trial. This means that instead of having one type of anti-cancer treatment in the period in which overall survival is assessed, participants can have multiple; the treatment which they received during the trial ('on-trial') and one or more which they received after they completed their trial treatment ('off-trial'). In the assessment of overall survival we are interested in the difference in outcome, if any, between the two types (experimental or control) of 'on-trial' treatment. However, the current methods available to analyse overall survival do not account for multiple lines of treatment. Therefore, the on-trial and off-trial treatment effects are combined together. This makes it difficult to work out what effect each line of treatment has on overall survival and in turn know whether a difference exists between the 'on-trial' treatments. This research is designed to tackle this problem. It will investigate methods that can be used to analyse overall survival in the event that some patients receive anti-cancer treatment off-trial. However, for the research to be relevant, is important that the new method gives an answer which is of interest to; patients, clinicians and health care regulators. Therefore a discussion will be organised to identify all the possible aspects which could be investigated. From these discussions the main priorities in terms of how to analyse overall survival and how to present the results will be identified and used guide the development of a new method.To evaluate whether the new method works, it will be tested on simulated data (data generated by a computer) and data collected in clinical trials. Using simulated data makes sure that the method works by identifying beforehand what we are looking for and checking that the new method can find it. The research will then be assessed by those who participated in the initial discussions. Any feedback will be discussed and incorporated where appropriate. Once agreed, sessions will be organised to promote and explain the method. In addition, statistical software will be written to make the method accessible to researchers. However, the method will only be useful if the data that it needs to work is available. Therefore part of this research will explore what data is normally collected on 'off-trial' participants and consider; what routine data sources currently exist and how researchers could access them. The overall aim of this research is to develop a method which assesses overall survival whilst accounting for 'off-trial' treatments. It is hoped that this method will be relevant, accessible and better inform decision makers on whether a new treatment should be approved.

Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: CANCER AND NEOPLASMS