Title: Development of a methodological framework to account for the impact of non-adherence on the cost-effectiveness of prescribed chronic medications
Funder: Department of Health and Social Care

Abstract: Background Non-adherence to medications is a major and intractable issue in health care, with significant negative consequences for both clinical outcomes and costs. The clinical consequences may be determined by three factors: (i) the types of non-adherence; (ii) the nature of disease; and (iii) the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug. The cost consequences are driven by reduced efficacy of the drug leading to an increased probability of therapeutic failure. Both clinical and cost consequences have a direct impact on cost-effectiveness.Randomised controlled trials (RCTs) are considered to represent the gold standard for estimating the treatment effect in the context of economic evaluations for Health Technology Assessment (HTA). However, a key issue with evidence from RCTs is related to generalisability to routine clinical practice. Non-adherence is a key factor which could impact on treatment effect as evidence suggests that the level of medication adherence in the real world is likely to differ from RCTs.The health economics literature has adopted five different methodological approaches to account for non-adherence: (1) regression-based covariate adjustment; (2) categorisation of patients into clusters with different levels of adherence; (3) incorporating adherence as a modifier in deriving the rates of transition between health states; (4) specifying adherence as an event within time-based simulation models; and (5) characterising the effect of non-adherence on PK/PD parameters, and therefore, on the treatment effect, with a modelled relationship between PK/PD and the treatment effect. However, this classification is not perfect as there is substantial overlap between theses methods and other methods will also exist (e.g. causal inference statistical methods).Despite the increased attention for modelling non-adherence in the health economics literature, methods to adjust for non-adherence remain underdeveloped, with no consensus on the appropriate methodological approach to deal with the key issues. The NICE Guide to Methods of Technology Appraisal (2013) recommends that the value of additional benefits from the mode of treatment delivery through its impact on adherence should be quantified. However, the guide does not mention any preferred method(s) for modelling non-adherence. There seems to be a gap in the health economics literature in conceptualising and modelling the link between non-adherence and treatment effect, and hence, the impact on cost-effectiveness.Aims The main question to be addressed by this research is How should economic evaluations incorporate the impact of non-adherence using evidence from both clinical trials and real-world data?. The aim is to develop a methodological framework to account for the impact of non-adherence on the cost-effectiveness of health technologies.Plan of investigation This research involves four linked stages: Systematic review to identify relevant methods used for modelling non-adherence and develop a new taxonomy of methods. Simulation study to assess the relative performance of alternative methods in estimating adherence-adjusted treatment effect. Case study for practical application of adjustment methods in kidney transplantation. Development of a methodological framework to account for non-adherence when undertaking cost-effectiveness analyses. Summary of the potential benefits to patients and the NHS This research will lead to potential benefits to patients and the NHS. The methodological framework which will be produced from this work will contribute to improvement in the overall quality of economic models used for estimating cost-effectiveness. This will contribute to improvement in the quality and relevance of cost-effectiveness evidence produced by academic researchers and the pharmaceutical industry with the level of non-adherence in the real world taken into account (which could be different from trials). This in turn will lead to cost savings for the NHS and/or improvement in health-related quality of life for patients who are affected by decisions made using the methodological framework.

Lay abstract: Background The problem of patients not taking their drugs as prescribed (known as non-adherence') is an important issue in health care. This problem has large negative effects on both health outcomes and costs. In England, findings from a study on the effects of non-adherence for five chronic diseases were striking. These diseases were: asthma, diabetes, schizophrenia, hypertension and heart-related diseases. For many of these diseases, the treatment cost to the NHS of non-adherence was valued to be more than 100 million per year. The losses to patients in terms of worse treatment outcomes as a result of non-adherence are also important. Kidney transplantation is an important area where the effects of non-adherence are very large. Non-adherence in patients after having kidney transplantation can be so serious that the transplanted kidney may be rejected, or they may need to return to intensive treatment (kidney dialysis) or they may even die.Controlled clinical studies, known as trials', are used as the best way of assessing treatment effects. However, there is a debate around whether evidence from trials can reflect normal health care practice. A major factor which could impact on treatment effect is patient non-adherence. Many methods have been suggested to account for the effects of non-adherence when assessing the value of new drugs - known as cost-effectiveness'. However, not enough is known about the link between non-adherence, health outcomes and cost-effectiveness. There is no agreement among researchers on how to address this problem.This problem raises a number of important research questions including: (1) What are the different methods used to account for the effects of non-adherence on treatment effects? (2) How good are they at accounting for non-adherence? and (3) How should cost-effectiveness studies account for patient non-adherence using evidence from both trials and the real world?Aim of the research The aim is to develop guidance for better assessment of cost-effectiveness to improve drug funding decisions and health outcomes. This will allow us to better assess the value of new drugs used for chronic diseases by taking into account their use in normal health care practice. The guidance will also help to assess the value of programmes that could improve adherence to prescribed drugs.Design and methods used The research will involve four stages. First, I will find methods used to account for non-adherence by looking at the existing research. Second, I will study each method and assess the most appropriate approaches using computer modelling. Third, I will apply these methods to a case study on kidney transplantation to show how they could be used to account for non-adherence. Finally, I will develop guidance for researchers who need to use these methods when conducting their own studies.Patient and public involvement and benefits to the NHS This research will benefit patients, the public and the NHS. The guidance will provide the scientific basis for researchers to account for the effects on non-adherence in cost-effectiveness analyses. This improved evidence about cost-effectiveness will lead to improved decision making around funding new and/or existing drugs. This is very important because patient experience of using drugs on everyday basis (which could differ from their experience during trials) will be taken into account when these important decisions are made. This could lead to cost savings to the NHS and/or gains in quality of life for patients taking drugs for chronic diseases.Patients have already been involved in the design of this research through two focus groups. This involvement will extend during the project using the same people and probably other people will get involved. I will do this by setting up a Patient and Public Involvement (PPI) group to provide advice throughout the lifetime of this research project (e.g. advice on what is the best measure of adherence).Dissemination I will publish the findings in four papers in major relevant journals. These will include guidance for researchers on how these methods could be used. The PPI group will advise on plain English summaries and best ways to spread the findings of this research to patients and the public. This could be through charities, voluntary organisations websites, and patient informal networks. This will inform patients' wider networks about this work and would help them in future engagement on this topic in other work.

Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: RENAL AND UROGENITAL