De Novo Cost-Effectiveness Model Framework for Nonalcoholic Steatohepatitis-Modeling Approach and Validation.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with hepatic morbidity and mortality and extra-hepatic comorbidities. Published NASH cost-effectiveness models (CEMs) are heterogeneous and consistently omit comorbid conditions that frequently co-exist alongside NASH. We aimed to develop a de novo CEM framework that incorporates extra-hepatic disease states and outcomes alongside hepatic components to enable future estimation of the cost-effectiveness of NASH interventions. METHODS: Patient-level simulation and cohort-level Markov models were implemented in the same framework. Model inputs included fibrosis progression; late-stage liver disease outcomes; comorbidity outcomes for cardiovascular disease, type 2 diabetes, and obesity; mortality; health-related quality of life; and direct medical costs. The prototype analysis assessed the cost-effectiveness of obeticholic acid versus standard of care from a US payer perspective over a lifetime horizon with costs and effects discounted at 3% per annum. However, the CEM was designed for easy adaptation to other countries, time horizons, and other considerations. Efficacy and adverse event parameters were obtained from the 18-month interim analysis of the REGENERATE trial. Outputs include total and incremental costs, total life years, and quality-adjusted life years. RESULTS: In this model, total costs, total life years, and quality-adjusted life years were all higher with obeticholic acid compared with standard of care. Cross-validation of this model with the 2016 and 2020 Institute for Clinical and Economic Review models revealed marked differences, mainly driven by mortality inputs, transition probability estimates, and incorporation of the effect of treatment and comorbidities. CONCLUSION: This is the first CEM in NASH to incorporate the clinical consequences of several comorbidities. The flexible yet standardized framework permits estimation of the cost-effectiveness of NASH interventions in a variety of settings. The model currently includes several assumptions and will be further developed as more relevant data become available.

The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England.

BACKGROUND: Nivolumab was the first programmed death receptor 1 (PD-1) immune checkpoint inhibitor to demonstrate long-term survival benefit in a clinical trial setting for advanced melanoma patients. OBJECTIVE: To evaluate the cost effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. METHODS: A Markov state-transition model was developed to estimate the lifetime costs and benefits of nivolumab versus ipilimumab and dacarbazine for BRAF mutation-negative patients and versus ipilimumab, dabrafenib, and vemurafenib for BRAF mutation-positive patients. Covariate-adjusted parametric curves for time to progression, pre-progression survival, and post-progression survival were fitted based on patient-level data from two trials and long-term ipilimumab survival data. Indirect treatment comparisons between nivolumab, ipilimumab, and dacarbazine were informed by these covariate-adjusted parametric curves, controlling for differences in patient characteristics. Kaplan-Meier data from the literature were digitised and used to fit progression-free and overall survival curves for dabrafenib and vemurafenib. Patient utilities and resource use data were based on trial data or the literature. Patients are assumed to receive nivolumab until there is no further clinical benefit, assumed to be the first of progressive disease, unacceptable toxicity, or 2 years of treatment. RESULTS: Nivolumab is the most cost-effective treatment option in BRAF mutation-negative and mutation-positive patients, with incremental cost-effectiveness ratios of £24,483 and £17,362 per quality-adjusted life year, respectively. The model results are most sensitive to assumptions regarding treatment duration for nivolumab and the parameters of the fitted parametric survival curves. CONCLUSIONS: Nivolumab is a cost-effective treatment for advanced melanoma patients in England.

A systematic review of cost-effectiveness modeling of pharmaceutical therapies in neuropathic pain: variation in practice, key challenges, and recommendations for the future.

OBJECTIVES: Complexities in the neuropathic-pain care pathway make the condition difficult to manage and difficult to capture in cost-effectiveness models. The aim of this study is to understand, through a systematic review of previous cost-effectiveness studies, some of the key strengths and limitations in data and modeling practices in neuropathic pain. Thus, the aim is to guide future research and practice to improve resource allocation decisions and encourage continued investment to find novel and effective treatments for patients with neuropathic pain. METHODS: The search strategy was designed to identify peer-reviewed cost-effectiveness evaluations of non-surgical, pharmaceutical therapies for neuropathic pain published since January 2000, accessing five key databases. All identified publications were reviewed and screened according to pre-defined eligibility criteria. Data extraction was designed to reflect key data challenges and approaches to modeling in neuropathic pain and based on published guidelines. RESULTS: The search strategy identified 20 cost-effectiveness analyses meeting the inclusion criteria, of which 14 had original model structures. Cost-effectiveness modeling in neuropathic pain is established and increasing across multiple jurisdictions; however, amongst these studies, there is substantial variation in modeling approach, and there are common limitations. Capturing the effect of treatments upon health outcomes, particularly health-related quality-of-life, is challenging, and the health effects of multiple lines of ineffective treatment, common for patients with neuropathic pain, have not been consistently or robustly modeled. CONCLUSIONS: To improve future economic modeling in neuropathic pain, further research is suggested into the effect of multiple lines of treatment and treatment failure upon patient outcomes and subsequent treatment effectiveness; the impact of treatment-emergent adverse events upon patient outcomes; and consistent and appropriate pain measures to inform models. The authors further encourage transparent reporting of inputs used to inform cost-effectiveness models, with robust, comprehensive and clear uncertainty analysis and, where feasible, open-source modeling is encouraged.

Preventive strategies for group B streptococcal and other bacterial infections in early infancy: cost effectiveness and value of information analyses.

OBJECTIVE: To determine the cost effectiveness of strategies for preventing neonatal infection with group B streptococci and other bacteria in the UK and the value of further information from research. DESIGN: Use of a decision model to compare the cost effectiveness of prenatal testing for group B streptococcal infection (by polymerase chain reaction or culture), prepartum antibiotic treatment (intravenous penicillin or oral erythromycin), and vaccination during pregnancy (not yet available) for serious bacterial infection in early infancy across 12 maternal risk groups. Model parameters were estimated using multi-parameter evidence synthesis to incorporate all relevant data inputs. DATA SOURCES: 32 systematic reviews were conducted: 14 integrated results from published studies, 24 involved analyses of primary datasets, and five included expert opinion. Main outcomes measures Healthcare costs per quality adjusted life year (QALY) gained. RESULTS: Current best practice (to treat only high risk women without prior testing for infection) and universal testing by culture or polymerase chain reaction were not cost effective options. Immediate extension of current best practice to treat all women with preterm and high risk term deliveries without testing (11% treated) would result in substantial net benefits. Currently, addition of culture testing for low risk term women, while treating all preterm and high risk term women, would be the most cost effective option (21% treated). If available in the future, vaccination combined with treating all preterm and high risk term women and no testing for low risk women would probably be marginally more cost effective and would limit antibiotic exposure to 11% of women. The value of information is highest (67m pounds sterling) if vaccination is included as an option. CONCLUSIONS: Extension of current best practice to treat all women with preterm and high risk term deliveries is readily achievable and would be beneficial. The choice between adding culture testing for low risk women or vaccination for all should be informed by further research. Trials to evaluate vaccine efficacy should be prioritised.

United Kingdom cervical cancer screening and the costs of time and travel.

OBJECTIVES: The aim of this study was to estimate the time and travel costs generated by women when attending for Papanicolaou (Pap) smear tests or colposcopy appointments in the United Kingdom, both absolutely and relative to the health service cost of the national cervical cancer screening programs. METHODS: Data were obtained from questionnaires completed by two samples of women participating in a three-center trial of management of low-grade abnormalities detected by screening (n = 1,106 for Pap smears and n = 1,203 for colposcopy appointments). Women were 20 to 59 years of age and resident in Grampian or Tayside, Scotland, or Nottingham, England. Questionnaire data were supplemented with sociodemographic information previously collected at the time of recruitment to the trial. RESULTS: The mean total time and travel costs per attendance at a smear test and at a colposcopy appointment were estimated to be 9.2 pounds and 27.4 pounds, respectively, averaged across the three trial areas (valued at 2002 prices). Statistically significant intercenter disparities in time and travel costs were identified, particularly with respect to colposcopy appointments. For these, time and travel costs in Nottingham were substantially less than those in Grampian and Tayside (22.9 pounds, 30.2 pounds, and 32.1 pounds, respectively). Time and travel costs amount to 26 and 33 percent, approximately, over and above the direct health service costs of the English and Scottish screening programs, respectively. CONCLUSIONS: The time and travel costs associated with participation in the UK cervical cancer screening programs are substantial and are not spatially uniform across the country.

Priority setting for research in health care: an application of value of information analysis to glycoprotein IIb/Illa antagonists in non-ST elevation acute coronary syndrome.

The purpose of this study is to explain the rationale for the value of information approach to priority setting for research and to describe the methods intuitively for those familiar with basic decision analytical modeling. A policy-relevant case study is used to show the feasibility of the method and to illustrate the type of output that is generated and how these might be used to frame research recommendations. The case study relates to the use of glycoprotein Ilb/Illa antagonists for the treatment of patients with non-ST elevation acute coronary syndrome. This is an area that recently has been appraised by the National Institute for Health and Clinical Excellence.

Introducing HPV triage into the English cervical cancer screening program: consequences for participation.

OBJECTIVE: To predict the likely impact of adding human papillomavirus (HPV) triage for minor abnormalities on participation in the English cervical cancer screening program. METHOD: Contingent valuations of the existing Pap program and a possible HPV-augmented screening program, obtained from questionnaires completed by 1141 women in east-central England. RESULTS: The value of participating in Pap screening was negatively associated with age, positively associated with educational level, and positively associated with the level of household income. Higher levels of worry about cervical cancer were associated with higher valuations of screening. Adding HPV-based triage to the Pap program lowered the value of screening participation for only two women, whereas for the sample as a whole, it increased the average valuation by about 47 percent. Supposedly-negative characteristics of HPV testing, when described, were expected to trigger psychosocial concerns in respondents and thereby give rise to significant decreases in valuations of participating in a Pap-plus-HPV program. For most women, however, such information changed their valuations of participation in screening little, if at all. CONCLUSIONS: Accepting the proposition that higher contingent valuations indicate stronger behavioural preferences, our results offer insubstantial grounds for believing that the inclusion of HPV triage would detrimentally affect participation in Pap screening for cervical cancer.

Good practice guidelines for decision-analytic modelling in health technology assessment: a review and consolidation of quality assessment.

The use of decision-analytic modelling for the purpose of health technology assessment (HTA) has increased dramatically in recent years. Several guidelines for best practice have emerged in the literature; however, there is no agreed standard for what constitutes a 'good model' or how models should be formally assessed. The objective of this paper is to identify, review and consolidate existing guidelines on the use of decision-analytic modelling for the purpose of HTA and to develop a consistent framework against which the quality of models may be assessed. The review and resultant framework are summarised under the three key themes of Structure, Data and Consistency. 'Structural' aspects relate to the scope and mathematical structure of the model including the strategies under evaluation. Issues covered under the general heading of 'Data' include data identification methods and how uncertainty should be addressed. 'Consistency' relates to the overall quality of the model. The review of existing guidelines showed that although authors may provide a consistent message regarding some aspects of modelling, such as the need for transparency, they are contradictory in other areas. Particular areas of disagreement are how data should be incorporated into models and how uncertainty should be assessed. For the purpose of evaluation, the resultant framework is applied to a decision-analytic model developed as part of an appraisal for the National Institute for Health and Clinical Excellence (NICE) in the UK. As a further assessment, the review based on the framework is compared with an assessment provided by an independent experienced modeller not using the framework. It is hoped that the framework developed here may form part of the appraisals process for assessment bodies such as NICE and decision models submitted to peer review journals. However, given the speed with which decision-modelling methodology advances, there is a need for its continual update.

Testing the construct validity of willingness to pay valuations using objective information about risk and health benefit.

This paper describes an experiment to test the construct validity of contingent valuation, by eliciting women's valuations for the NHS cervical cancer screening programme. It is known that, owing to low levels of knowledge of cancer and screening in the general population, women both over-estimate the risk of disease and the efficacy of screening. The study is constructed as a randomised experiment, in which one group is provided with accurate information about cervical cancer screening, whilst the other is not. The first hypothesis supporting construct validity, that controls who perceive greater benefits from screening will offer higher valuations, is substantiated. Both groups are then provided with objective information on an improvement to the screening programme, and are asked to value the improvement as an increment to their original valuations. The second hypothesis supporting construct validity, that controls who perceive the benefits of the programme to be high already will offer lower incremental valuations, is also substantiated.

Think of a number... any number?

An examination of the willingness to pay values elicited from more than 3000 persons involved in three independent studies revealed that the majority had offered one of a limited number of values from the ranges available to them. These values were 'prominent numbers', the use of which has been observed previously in circumstances where subjects feel that precise estimates of value are either difficult to make, or are not worth making. The existence of widespread prominence in response is suggestive of hypothetical bias in contingent valuation.

Management of non-ST-elevation acute coronary syndromes: how cost-effective are glycoprotein IIb/IIIA antagonists in the UK National Health Service?

BACKGROUND: The glycoprotein IIb/IIIa antagonists (GPAs) represent a new class of drugs to prevent platelet aggregation in the acute treatment of non-ST-elevation acute coronary syndromes (NSTE-ACS). Systematic reviews have identified serious limitations in published cost-effectiveness analyses, including a lack of UK-specific studies and an absence of studies comparing different protocols for the use of GPAs. METHODS: A model was developed to assess the cost effectiveness of a variety of protocols employing GPAs for patients presenting with NSTE-ACS in the UK. The perspective of the UK National Health Service was adopted, with outcomes in terms of quality-adjusted life-years (QALYs). Four treatment strategies were evaluated: GPAs as part of initial medical management (Strategy 1); GPAs in patients with planned percutaneous coronary interventions (PCIs; Strategy 2); GPAs as an adjunct to the PCI procedure (Strategy 3); and no GPAs (Strategy 4). Baseline event rates and costs were taken from a UK observational study of ACS patients and relative risk reductions from GPAs were taken from a meta analysis of trials. Long-term costs and QALYs were estimated using data from a UK longitudinal study. RESULTS: The most cost-effective use of GPAs is likely to be Strategy 1, with an incremental cost per QALY gained of between pound4605 to pound10,343. Focusing this use of GPAs only on the subgroup of patients at high risk appears to represent the most cost-effective use of NHS resources. CONCLUSIONS: Medical management of patients with NSTE-ACS using GPAs is the most cost-effective use of resources, particularly if targeted to higher risk subgroups.

Diagnosing infertility in a district general hospital: a case-note and cost analysis.

This study aimed to observe diagnostic work-up and cost evaluation of infertile couples to identify opportunities for improvement. One hundred and seventy-four new referrals to the gynaecology clinic in a District General Hospital during 1996 and 1997 provided the cohort for analysis. Data from case notes were transferred on to data collection sheets. Data were inputted into SPSS for analysis. Primary infertility accounted for 62% of couples. One hundred and forty-two couples (81.6%) had a definitive diagnosis, and the analyses relate to these couples only. There was no single investigation performed on the whole cohort studied. Semen analysis was undertaken in 80.3% of the couples; couples with suspected male infertility were over four times more likely to have had more than two semen tests (P = 0.0005); 77.5% of couples had FSH and LH tests; and midluteal progesterone was tested in 76.1%. An increased intensity of FSH-LH hormone testing was associated with couples with anovulation (chi(2) = 6.79, P = 0.03). Serial repeat progesterone tended to be given to women with irregular or prolonged cycles (35 days or more), although this tendency was not statistically significant. The most common test for tubal patency was hysterosalpingography. Higher costs are generally associated with diagnosing endometriosis and tubal factor because of the relatively high cost of laparoscopy. The average cost of diagnosis for each patient was pound 365 and ranged from pound 64 to pound 851. In conclusion, a standard protocol of basic investigative procedures should be offered in secondary centres to all couples. Avoiding duplication and unnecessary investigations (for example, serial progesterone) may reduce costs, although offering all couples a standard protocol of tests would probably offset this observation.

Human papillomavirus and the value of screening: young women's knowledge of cervical cancer.

The study reports a questionnaire survey of female university students intended (1) to delineate their knowledge of cervical cancer and screening, and (2) to impute their valuation of the introduction of human papillomavirus (HPV) testing. It was found that almost 80% of respondents thought cervical cancer was a leading cause of cancer death amongst women. Most subjects consistently over-estimated the incidence of cervical cancer, consistent with the social amplification hypothesis. The major risk factors were accurately identified by the majority, although family history was emphasized to a degree unwarranted by epidemiological evidence. Subjects' knowledge of the screening programme was accurate in some respects, but not in others, e.g. the majority under-estimated the abnormality rate and over-estimated the age at which abnormalities typically occurred. Subjects placed a premium on the increased accuracy which HPV testing might potentially offer, predictable from their beliefs about the performance of the existing screening programme. Policy makers can be reassured that female university students appear unconcerned about undergoing a test for a sexually transmitted disease, although their beliefs about cervical cancer and the power of screening are distorted, and their enthusiasm for HPV testing relates to an, as yet, unconfirmed belief in its accuracy.

Psychosocial and economic aspects of a trial of management of mild and borderline cervical abnormalities (TOMBOLA).

TOMBOLA is a randomized controlled trial to determine (a) the most effective and efficient management strategy for women with borderline or mildly dyskaryotic cervical smear results, and (b) the most appropriate treatment for women with abnormalities detected following colposcopy. This paper outlines the trial's psychosocial and economic protocol, and explains how TOMBOLA can provide detailed evidence on the psychosocial and economic impact of alternative management options and follow-up. This protocol has been developed in parallel with the clinical protocol, thereby offering the opportunity for the development of a type-specific outcome measure and detailed piloting of all instruments. The multi-disciplinary approach to TOMBOLA allows the combination of clinical outcomes with both generic and specific psychosocial and health-related quality of life measures. The convergent validity between these measures will be assessed, with a view to developing a specific utility index for the future assessment of cervical screening modalities.