Jeff Round

Behavioural and psychiatric symptoms in people with dementia admitted to the acute hospital: prospective cohort study.

BACKGROUND Dementia is common in older people admitted to acute hospitals. There are concerns about the quality of care they receive. Behavioural and psychiatric symptoms of dementia (BPSD) seem to be particularly challenging for hospital staff. AIMS To define the prevalence of BPSD and explore their clinical associations. METHOD Longitudinal cohort study of 230 people with dementia, aged over 70, admitted to hospital for acute medical illness, and assessed for BPSD at admission and every 4 (± 1) days until discharge. Other measures included length of stay, care quality indicators, adverse events and mortality. RESULTS Participants were very impaired; 46% at Functional Assessment Staging Scale (FAST) stage 6d or above (doubly incontinent), 75% had BPSD, and 43% had some BPSD that were moderately/severely troubling to staff. Most common were aggression (57%), activity disturbance (44%), sleep disturbance (42%) and anxiety (35%). CONCLUSIONS We found that BPSD are very common in older people admitted to an acute hospital. Patients and staff would benefit from more specialist psychiatric support.

Updated Cost-Effectiveness Analysis of Trastuzumab for Early Breast Cancer A UK Perspective Considering Duration of Benefit, Long-Term Toxicity and Pattern of Recurrence

AbstractBackground: Trastuzumab has significantly improved survival outcomes for women with Human Epidermal growth factor Receptor 2 (HER2)-positive early breast cancer. Trastuzumab was established as a cost-effective adjuvant treatment in 2006. We present an updated cost-effectiveness analysis from the UK perspective, which explores assumptions about the duration of benefit from treatment, pattern of metastatic recurrence and long-term cardiac toxicity. Objective: The objective of this study was to calculate, from the UK NHS perspective, expected costs (year 2008 values) and benefits over the lifetime of an average cohort of women with HER2-positive early breast cancer treated with or without 1 year of adjuvant trastuzumab sequentially after chemotherapy. Methods: A cost-utility analysis was performed using a discrete-state timedependent semi-Markov model. Probabilistic sensitivity analysis was used to characterize uncertainty around expected outcomes. Value-of-information (VOI) analysis was used to identify areas of priority for further research. Results: The cost-effectiveness estimates were highly sensitive to the estimated duration of treatment benefit. Trastuzumab remained a cost-effective treatment strategy at a willingness-to-pay threshold of £30000 per QALY provided the duration of benefit was more than 3.6 years from treatment initiation, assuming the hazard ratio for disease-free survival was 0.63. An increasing proportion of brain metastases with trastuzumab produced a small change towards worse cost effectiveness. Long-term cardiac toxicity needed to rise to high levels to affect overall life expectancy and cost effectiveness. VOI analysis placed highest value on research into the duration of treatment benefit. The relationships between progression-free survival and overall survival and the costs of cancer recurrence were also important. Conclusion: The cost effectiveness of adjuvant trastuzumab remains uncertain and dependent on assumptions regarding its clinical effect. Uncertainty around cost effectiveness could be reduced by further research into the duration of treatment effect, particularly in subgroups where this may be shorter. Longterm follow-up is warranted and methods to accurately measure duration of treatment effect and late toxicities should be developed for future adjuvant drug studies.

An early evaluation of clinical and economic costs and benefits of implementing point of care NAAT tests for Chlamydia trachomatis and Neisseria gonorrhoea in genitourinary medicine clinics in England

Objectives To estimate the costs and benefits of clinical pathways incorporating a point of care (POC) nucleic acid amplification test (NAAT) for chlamydia and gonorrhoea in genitourinary medicine (GUM) clinics compared with standard off-site laboratory testing. Method We simulated 1.2 million GUM clinic attendees in England. A simulation in Microsoft Excel was developed to compare existing standard pathways of management for chlamydia and gonorrhoea with a POC NAAT. We conducted scenario analyses to evaluate the robustness of the model findings. The primary outcome was the incremental cost-effectiveness ratio. Secondary outcomes included the number of inappropriate treatments, complications and transmissions averted. Results The baseline cost of using the point of POC NAAT was £103.9 million compared with £115.6 million for standard care. The POC NAAT was also associated with a small increase of 46 quality adjusted life years, making the new test both more effective and cheaper. Over 95 000 inappropriate treatments might be avoided by using a POC NAAT. Patients receive diagnosis and treatment on the same day as testing, which may also prevent 189 cases of pelvic inflammatory disease and 17 561 onward transmissions annually. Discussion Replacing standard laboratory tests for chlamydia and gonorrhoea with a POC test could be cost saving and patients would benefit from more accurate diagnosis and less unnecessary treatment. Overtreatment currently accounts for about a tenth of the reported treatments for chlamydia and gonorrhoea and POC NAATs would effectively eliminate the need for presumptive treatment.

Sorafenib for the treatment of advanced hepatocellular carcinoma.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of sorafenib according to its licensed indication for advanced hepatocellular carcinoma (HCC). The ERG report was based on the manufacturers submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The licensed indication for sorafenib specifies advanced HCC patients for whom locoregional intervention and surgery are unsuitable or had been unsuccessful. The clinical evidence came from a multicentre randomised controlled trial (Sorafenib HCC Assessment Randomized Protocol; SHARP) of sorafenib plus best supportive care versus placebo plus best supportive care, with 602 participants of a predominantly European ethnicity broadly comparable to the UK population. The submitted evidence indicated that for advanced HCC patients with Child-Pugh grade A liver function and relatively good Eastern Cooperative Oncology Group performance status, sorafenib on average improves overall survival by 83 days relative to placebo, and also increases time-to-radiological disease progression. Sorafenib therapy had little or no effect on time-to-symptom progression or on quality of life as measured using a disease-specific questionnaire. Sorafenib treatment was associated with increased incidence of hypertension and of gastrointestinal and dermatological problems. However, the therapy was reasonably well tolerated and, in SHARP, withdrawals from treatment due to adverse events were similar in the sorafenib and placebo arms, although more temporary reductions in dose were required in the sorafenib than in the placebo group. In the base case, the manufacturers submitted economic analysis generated a deterministic incremental cost-effectiveness ratio (ICER) of 64,754 pounds per quality-adjusted life-year (QALY). The ERG extracted individual patient data for overall survival and disease progression, reran the economic model to check the submitted cost-effectiveness results, and performed new analyses which the ERG considered relevant to the decision problem; these analyses delivered ICERs between 76,000 pounds/QALY and 86,000 pounds/QALY. The guidance issued by NICE (7 May 2009) stated that sorafenib, within its licensed indication, is not recommended for the treatment of advanced (Barcelona-Clínic Liver Cancer stage C) HCC patients for whom surgical or locoregional therapies have failed or are not suitable, and people currently receiving sorafenib for the treatment of HCC should have the option to continue treatment until they and their clinician consider it appropriate to stop. Subsequently the manufacturer submitted a patient access scheme to the Department of Health. The base-case ICER submitted by the manufacturer for this scheme was 51,899 pounds/QALY. When the ERG reran the model with inputs considered relevant to the decision problem the ICER estimates ranged between 53,000 pounds to 58,000 pounds/QALY and substantially higher values depending on the nature of the sensitivity analyses. NICE considered the impact of the patient access scheme and determined that it was not sufficient to alter the guidance.

Urinary tract infections in children and the risk of ESRF.

Aims:  Paediatric guidance on diagnosis and treatment of urinary tract infections (UTIs) has in the past largely focused on identifying children with vesicoureteral reflux, thought to be at greatest risk of renal scarring. This practice has been questioned, specifically the accepted association between UTI and end‐stage renal failure (ESRF) through renal scarring. The aim of this article is to ascertain whether we can predict with confidence the true level of risk that a child with a first‐time UTI will subsequently develop ESRF attributable to UTI.

An Educational Review of the Statistical Issues in Analysing Utility Data for Cost-Utility Analysis

The aim of cost-utility analysis is to support decision making in healthcare by providing a standardised mechanism for comparing resource use and health outcomes across programmes of work. The focus of this paper is the denominator of the cost-utility analysis, specifically the methodology and statistical challenges associated with calculating QALYs from patient-level data collected as part of a trial. We provide a brief description of the most common questionnaire used to calculate patient level utility scores, the EQ-5D, followed by a discussion of other ways to calculate patient level utility scores alongside a trial including other generic measures of health-related quality of life and condition- and population-specific questionnaires. Detail is provided on how to calculate the mean QALYs per patient, including discounting, adjusting for baseline differences in utility scores and a discussion of the implications of different methods for handling missing data. The methods are demonstrated using data from a trial. As the methods chosen can systematically change the results of the analysis, it is important that standardised methods such as patient-level analysis are adhered to as best as possible. Regardless, researchers need to ensure that they are sufficiently transparent about the methods they use so as to provide the best possible information to aid in healthcare decision making.

Estimating the cost of caring for people with cancer at the end of life: A modelling study.

Background: People with advanced cancer require a range of health, social and informal care during the final phases of life. The cost of providing care to this group as they approach the end of their lives is unknown, but represents a significant cost to health and social care systems, charities patients and their families. Aim: In this study, we estimate the direct and indirect costs for lung, breast, colorectal and prostate cancer patients at the end of life (from the start of strong opioids to death) in England and Wales. Methods: We use a modelling-based approach to estimate the costs of care. Data are estimated from the literature and publicly available data sets. Probabilistic sensitivity analysis is used to reflect uncertainty in model estimates. Results: Total estimated costs for treating people with these four cancers at the end of life are £641 million. Breast and prostate cancer patients have the highest expected cost per person at £12,663 (95% credible interval (CI): £1249–£38,712) and £14,859 (95% CI: £1391–£46,424), respectively. Lung cancer has the highest expected total cost (£226m). The value of informal care giving accounts for approximately one-third of all costs. Conclusion: The cost to society of providing care to people at the end of their lives is significant. Much of this cost is borne by informal care givers. The cost to formal care services of replacing this care with paid care giving would be significant and demand for care will increase as the demographic profile of the population ages.

Economic Considerations in the Provision of Treatments for Rare Diseases

Orphan Drug legislation in the USA, Europe and elsewhere has been incredibly successful in promoting the development of new treatments for rare diseases. Historically, payers have constructed special schemes that have facilitated patient access given the small total budget impact of these treatments. However, whilst each disease is rare, the number of licensed orphan drugs is growing rapidly. This, in conjunction with the high prices claimed for these treatments, has increased the total budget impact of orphan drugs. In the medium term, the feasibility of omitting orphan drugs from value for money type assessments is doubtful. The arguments for a special status for orphan drugs in reimbursement processes are reviewed in this article, and it is concluded that these arguments do not generally stand up to critical assessment. A new paradigm for the development and purchase of orphan drugs may be required. Given the strong parallels between the challenges of neglected diseases in developing countries and orphan diseases in developed countries, policy tools developed for neglected diseases; such as Public Private Partnerships and Advance Market Commitments, might be fruitfully applied in the orphan drug arena.

Lancet Commission: Stem cells and regenerative medicine

In this Commission, we argue that a combination of poor quality science, unclear funding models, unrealistic hopes, and unscrupulous private clinics threatens regenerative medicines social licence to operate. If regenerative medicine is to shift from mostly small-scale bespoke experimental interventions into routine clinical practice, substantial rethinking of the social contract that supports such research and clinical practice in the public arena will be required. For decades, stem cell therapy was predominantly limited to bone marrow transplantation for haematological diseases and epidermis transplantation for large burns. Tissue engineering and gene therapy faced huge challenges on their way to clinical translation—a situation that began to change only at the end of the 1990s. The past 10 years have seen an exponential growth in experimental therapies, broadly defined as regenerative medicine, entering the clinical arena. Results vary from unequivocal clinical efficacy for previously incurable and devastating diseases to (more frequently) a modest or null effect. The reasons for these widely different outcomes are starting to emerge. At this stage in their evolution, these experimental therapies (which include, but are not limited to, cell and gene therapy, tissue engineering, and new generation drugs) are necessarily financially expensive. Rigorous and costly clinical-grade procedures have to be followed in the development of medicinal products (involving cells, genetically manipulated cells, viral vectors, or biomaterials with or without cells), often produced in a very limited run. The cost of developing sufficiently high-quality trials means that only wealthier countries are able to fund them. Although public investments in this field are massive internationally, they do not carry guaranteed commercial returns. Compared with conventional drug development, such products follow a highly uncertain route to market. Furthermore, new therapies expose patients to risks, some of which are difficult to predict even with inbuilt safeguards. Despite the relatively small number of clinical successes, optimism and excitement about the potential effect or implications of this field remain great. This enthusiasm has led to gaps between peoples expectations that new therapies should be available, often inflated by media reports, and the realities of translating regenerative technologies into clinical practice. The same environment is also permissive of one-off compassionate applications and poorly regulated trials. Indeed, the number of poorly regulated clinics has grown; clinics that appeal to desperate patients and their families, who, in the absence of reliable clinical knowledge from trials, cannot be adequately informed to assess the risks and benefits. These ethical and governance issues pose a challenge to scientists in engaging with the public, the press, and decision-making bodies in different national health systems. Political agendas might not coincide with the public good. In poorly regulated states, the authorisation of a novel therapy might be politically attractive, even when efficacy is unconfirmed, and the cost to taxpayers means other patients are deprived of established and effective therapies. These challenges are difficult to address and solve. We recommend a solution that lies in a coordinated strategy with four pillars: better science, better funding models, better governance, and better public and patient engagement.

A framework for understanding quality of life in individuals without capacity

AbstractPurposeThe wide range of tools and methods developed for measuring and valuing health-related quality of life for use in economic evaluations are appropriate for use in most populations. However, for certain populations, specific tools may need to be developed to reflect the particular needs of that population. Patients without capacity—particularly patients with severe dementia—are such a population. At present, the tools available to economists for measuring and valuing quality of life in these patients lack validity. Here, we seek to understand the framework within which common instruments have been developed, critique these instruments with respect to patients with severely restricted capacity and to develop a new way of thinking about how to value health-related quality of life in such patients. MethodIn this essay, we describe and critique the conceptual framework by which common instruments used for measuring and valuing quality of life have been developed.ResultsWe show that current common instruments used for measuring and valuing quality of life in general populations are not appropriate for populations with severely restricted capacity.ConclusionsWe propose a new framework for thinking about quality of life in this population, based on notions of observable person-centred outcomes and utility derived from processes of care.