Estimating outcomes and cost effectiveness using a single-arm clinical trial: ofatumumab for double-refractory chronic lymphocytic leukemia.

BACKGROUND: Ofatumumab (Arzerra®, Novartis) is a treatment for chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab [double refractory (DR-CLL)]. Ofatumumab was licensed on the basis of an uncontrolled Phase II study, Hx-CD20-406, in which patients receiving ofatumumab survived for a median of 13.9 months. However, the lack of an internal control arm presents an obstacle for the estimation of comparative effectiveness. METHODS: The objective of the study was to present a method to estimate the cost effectiveness of ofatumumab in the treatment of DR-CLL. As no suitable historical control was available for modelling, the outcomes from non-responders to ofatumumab were used to model the effect of best supportive care (BSC). This was done via a Cox regression to control for differences in baseline characteristics between groups. This analysis was included in a partitioned survival model built in Microsoft® Excel with utilities and costs taken from published sources, with costs and quality-adjusted life years (QALYs) were discounted at a rate of 3.5% per annum. RESULTS: Using the outcomes seen in non-responders, ofatumumab is expected to add approximately 0.62 life years (1.50 vs. 0.88). Using published utility values this translates to an additional 0.30 QALYs (0.77 vs. 0.47). At the list price, ofatumumab had a cost per QALY of £130,563, and a cost per life year of £63,542. The model was sensitive to changes in assumptions regarding overall survival estimates and utility values. CONCLUSIONS: This study demonstrates the potential of using data for non-responders to model outcomes for BSC in cost-effectiveness evaluations based on single-arm trials. Further research is needed on the estimation of comparative effectiveness using uncontrolled clinical studies.

Predictors of care home and hospital admissions and their costs for older people with Alzheimer's disease: findings from a large London case register.

OBJECTIVES: To examine links between clinical and other characteristics of people with Alzheimer's disease living in the community, likelihood of care home or hospital admission, and associated costs. DESIGN: Observational data extracted from clinical records using natural language processing and Hospital Episode Statistics. Statistical analyses examined effects of cognition, physical health, mental health, sociodemographic factors and living circumstances on risk of admission to care home or hospital over 6 months and associated costs, adjusting for repeated observations. SETTING: Catchment area for South London and Maudsley National Health Service Foundation Trust, provider for 1.2 million people in Southeast London. PARTICIPANTS: Every individual with diagnosis of Alzheimer's disease seen and treated by mental health services in the catchment area, with at least one rating of cognition, not resident in care home at time of assessment (n=3075). INTERVENTIONS: Usual treatment. MAIN OUTCOME MEASURES: Risk of admission to, and days spent in three settings during 6-month period following routine clinical assessment: care home, mental health inpatient care and general hospital inpatient care. RESULTS: Predictors of probability of care home or hospital admission and/or associated costs over 6 months include cognition, functional problems, agitation, depression, physical illness, previous hospitalisations, age, gender, ethnicity, living alone and having a partner. Patterns of association differed considerably by destination. CONCLUSIONS: Most people with dementia prefer to remain in their own homes, and funding bodies see this as cheaper than institutionalisation. Better treatment in the community that reduces health and social care needs of Alzheimer's patients would reduce admission rates. Living alone, poor living circumstances and functional problems all raise admission rates, and so major cuts in social care budgets increase the risk of high-cost admissions which older people do not want. Routinely collected data can be used to reveal local patterns of admission and costs.

Evaluating disease-modifying agents: a simulation framework for Alzheimer's disease.

BACKGROUND: Considerable advances have been made in modeling Alzheimer's disease (AD), with a move towards individual-level rather than cohort models and simulations that consider multiple dimensions when evaluating disease severity. However, the possibility that disease-modifying agents (DMAs) may emerge requires an update of existing modeling frameworks. OBJECTIVES: The aim of this study was to develop a simulation allowing for economic evaluation of DMAs in AD. METHODS: The model was developed based on a previously published, well-validated, discrete event simulation which measures disease severity on the basis of cognition, behaviour, and function, and captures the interrelated changes in these measures for individuals. The updated model adds one more domain, patient dependence, in addition to cognition, behaviour, and function to better characterize disease severity. Furthermore, the model was modified to have greater flexibility in assessing the impact of various important assumptions, such as the long-term effectiveness of DMAs and their impact on survival, on model outcomes. A validation analysis was performed to examine how well the model predicted change in disease severity among patients not receiving DMA treatment by comparing model results to those observed in two recent phase III clinical trials of bapineuzumab. In addition, various hypothetical scenarios were tested to demonstrate the improved features of the model. RESULTS: Validation results show that the model closely predicts the mean changes in disease severity over 18 months. Results from different hypothetical scenarios show that the model allows for credible assessment of those major uncertainties surrounding the long-term effectiveness of DMAs, including the potential impact of improved survival with DMA treatment. They also indicate that varying these assumptions could have a major impact on the value of DMAs. CONCLUSIONS: The updated economic model has good predictive power, but validation against longer-term outcomes is still needed. Our analyses also demonstrate the importance of designing a model with sufficient flexibility such that the model allows for assessment of the impact of key sources of uncertainty on the value of DMAs.

Utility elicitation study in the UK general public for late-stage chronic lymphocytic leukaemia.

OBJECTIVES: In the United Kingdom (UK), chronic lymphocytic leukaemia (CLL) makes up 40 % of all leukaemias in patients over 65 years. The study objective was to obtain societal preferences in the UK for "progression-free" and "progressive" states of late-stage CLL, refractory to current first and second line regimens. Preferences were also obtained for selected treatment-related adverse events (AEs). METHODS: A utility elicitation study, using the time trade-off (TTO) method, was conducted by face-to-face interviews with 110 subjects for a baseline disease state (before treatment), three primary disease states [progression-free survival (PFS) and treatment responder, PFS and treatment non-responder and disease progression], and 4 AE sub-states (PFS responder with thrombocytopenia, neutropenia, and infection, and PFS non-responder with infection). TTO scores were converted into utility values, and disutilities were calculated for AEs. Visual analogue scale (VAS) scores were obtained. RESULTS: The primary disease state mean TTO utility scores were: baseline: 0.549; PFS response: 0.671; PFS non-response: 0.394; and progression: 0.214. The mean TTO utility (disutility) scores for the AEs were: PFS response with thrombocytopenia, 0.563 (-0.108), neutropenia, 0.508 (-0.163), and infection, 0.476 (-0.195); PFS non-response with infection, 0.333 (-0.061). The VAS results were in line with the TTO results. CONCLUSIONS: The utility was higher for the PFS state than baseline, but decreased below baseline in non-response and disease progression states. AEs had an impact on utility within the PFS response state. The severe infection AE had a greater impact on utilities for the responding to treatment state compared to the non-responder state.

Treatment practices in adults with chronic immune thrombocytopenia - a European perspective.

Immune thrombocytopenia (ITP) is characterised by platelet destruction and impaired production leading to isolated thrombocytopenia. The aim of this study, comprising a retrospective longitudinal cohort study complemented by a Delphi panel of 35 physicians, was to describe standard treatment practices and treating physician's perception and preferences for available treatment options in chronic ITP. The medical records of 610 patients were reviewed over 12 months. Mean age at the start of the observational period was 54.6 yr, median platelet count 77 x 10(9)/L with 41% of patients having symptoms of ITP. Treated patients (61%) received an average of 2.7 medications either for ITP or ITP treatment-related side effects. An array of products was used, but the most frequent were corticosteroids. Delphi panel physicians (45%) indicated the main goals for treatment were to increase platelet levels to at least 30 x 10(9)/L to prevent bleeding or haemorrhage. The majority (89%) indicated that personal experience influenced treatment choice. Most (>80%) rated splenectomy and high-dose corticosteroids as the most effective but were concerned about side effects, and many (75%) would like access to interventions with improved efficacy and safety. The study highlights the need for updated evidence-based treatment guidelines to assist physicians in patient treatment decisions and to realise improvements in patient outcomes. It also identified perceived shortcomings of existing therapies and the need to establish an evidence base for newer interventions that could potentially make lasting response to treatment with fewer adverse effects an achievable goal.

Fluorescence-guided transurethral resection of bladder cancer using hexaminolevulinate: analysis of health economic impact in Sweden.

OBJECTIVE: A decision analytic model was established to estimate the budget impact on the Swedish health service of using hexaminolevulinate (HAL) in conjunction with white light cystoscopy (WLC) in the management of bladder cancer for 1 year following initial diagnosis. MATERIAL AND METHODS: Flowcharts were developed to represent the diagnostic and treatment pathways for each of four risk groups for non-muscle-invasive bladder cancer (NMIBC), as defined by risk of tumour recurrence and progression. Flowcharts were based on European Association of Urology Guidelines and adjusted to current Swedish clinical practice. The model covers the use of HAL cystoscopy in the operating room to guide transurethral resection of the bladder (TURB) in all patients. HAL cystoscopy as an adjunct to WLC allows for more accurate and complete resection of tumours compared with WLC alone, and the model assumed a consequent reduction in recurrence of 40%. RESULTS: The model projects that compared with WLC alone, use of HAL cystoscopy in the first TURB of all patients and for all TURBs due to recurrence in the first year after diagnosis, leads to a reduction of 23 cystectomies and 180 TURBs in a population of 2032 newly diagnosed bladder cancer patients. Avoidance of these procedures would result in a saving of SEK1 321 716 to the Swedish health service. CONCLUSION: HAL cystoscopy, used as an adjunct to white light in guiding TURB in NMIBC patients, may result in reduction of invasive, time-intensive and high-cost procedures such as cystectomy and TURB, compared with WLC alone.