Establishing the Value of Diagnostic and Prognostic Tests in Health Technology Assessment.

In recent years, Health Technology Assessment (HTA) processes specific to diagnostics and prognostic tests have been created in response to the increased pressure on health systems to decide not only which tests should be used in practice but also the best way to proceed, clinically, from the information they provide. These technologies differ in the way value is accrued to the population of users, depending critically on the value of downstream health care choices. This paper defines an analytical framework for establishing the value of diagnostic and prognostic tests for HTA in a way that is consistent with methods used for the evaluation of other health care technologies. It assumes a linked-evidence approach where modeling is required, and incorporates considerations regarding several different areas of policy, such as personalized medicine. We initially focus on diagnostic technologies with dichotomous results, and then extend the framework by considering diagnostic tests that provide more complex information, such as continuous measures (for example, blood glucose measurements) or multiple categories (such as tumor classification systems). We also consider how the methods of assessment differ for prognostic information or for diagnostics without a reference standard. Throughout, we propose innovative graphical ways of summarizing the results of such complex assessments of value.

Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate Cancer (STAMPEDE): Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness.

BACKGROUND: Results from large randomised controlled trials have shown that adding docetaxel to the standard of care (SOC) for men initiating hormone therapy for prostate cancer (PC) prolongs survival for those with metastatic disease and prolongs failure-free survival for those without. To date there has been no formal assessment of whether funding docetaxel in this setting represents an appropriate use of UK National Health Service (NHS) resources. OBJECTIVE: To assess whether administering docetaxel to men with PC starting long-term hormone therapy is cost-effective in a UK setting. DESIGN, SETTING, AND PARTICIPANTS: We modelled health outcomes and costs in the UK NHS using data collected within the STAMPEDE trial, which enrolled men with high-risk, locally advanced metastatic or recurrent PC starting first-line hormone therapy. INTERVENTION: SOC was hormone therapy for ≥2 yr and radiotherapy in some patients. Docetaxel (75mg/m2) was administered alongside SOC for six three-weekly cycles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The model generated lifetime predictions of costs, changes in survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS AND LIMITATIONS: The model predicted that docetaxel would extend survival (discounted quality-adjusted survival) by 0.89 yr (0.51) for metastatic PC and 0.78 yr (0.39) for nonmetastatic PC, and would be cost-effective in metastatic PC (ICER £5514/QALY vs SOC) and nonmetastatic PC (higher QALYs, lower costs vs SOC). Docetaxel remained cost-effective in nonmetastatic PC when the assumption of no survival advantage was modelled. CONCLUSIONS: Docetaxel is cost-effective among patients with nonmetastatic and metastatic PC in a UK setting. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in patients with nonmetastatic PC, as the opportunity to offer docetaxel at hormone therapy initiation will be missed for some patients by the time more mature survival data are available. PATIENT SUMMARY: Starting docetaxel chemotherapy alongside hormone therapy represents a good use of UK National Health Service resources for patients with prostate cancer that is high risk or has spread to other parts of the body.

Optimising the Diagnosis of Prostate Cancer in the Era of Multiparametric Magnetic Resonance Imaging: A Cost-effectiveness Analysis Based on the Prostate MR Imaging Study (PROMIS).

BACKGROUND: The current recommendation of using transrectal ultrasound-guided biopsy (TRUSB) to diagnose prostate cancer misses clinically significant (CS) cancers. More sensitive biopsies (eg, template prostate mapping biopsy [TPMB]) are too resource intensive for routine use, and there is little evidence on multiparametric magnetic resonance imaging (MPMRI). OBJECTIVE: To identify the most effective and cost-effective way of using these tests to detect CS prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Cost-effectiveness modelling of health outcomes and costs of men referred to secondary care with a suspicion of prostate cancer prior to any biopsy in the UK National Health Service using information from the diagnostic Prostate MR Imaging Study (PROMIS). INTERVENTION: Combinations of MPMRI, TRUSB, and TPMB, using different definitions and diagnostic cut-offs for CS cancer. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Strategies that detect the most CS cancers given testing costs, and incremental cost-effectiveness ratios (ICERs) in quality-adjusted life years (QALYs) given long-term costs. RESULTS AND LIMITATIONS: The use of MPMRI first and then up to two MRI-targeted TRUSBs detects more CS cancers per pound spent than a strategy using TRUSB first (sensitivity = 0.95 [95% confidence interval {CI} 0.92-0.98] vs 0.91 [95% CI 0.86-0.94]) and is cost effective (ICER = £7,076 [€8350/QALY gained]). The limitations stem from the evidence base in the accuracy of MRI-targeted biopsy and the long-term outcomes of men with CS prostate cancer. CONCLUSIONS: An MPMRI-first strategy is effective and cost effective for the diagnosis of CS prostate cancer. These findings are sensitive to the test costs, sensitivity of MRI-targeted TRUSB, and long-term outcomes of men with cancer, which warrant more empirical research. This analysis can inform the development of clinical guidelines. PATIENT SUMMARY: We found that, under certain assumptions, the use of multiparametric magnetic resonance imaging first and then up to two transrectal ultrasound-guided biopsy is better than the current clinical standard and is good value for money.

Are policy decisions on surgical procedures informed by robust economic evidence? A systematic review.

OBJECTIVES: The aim of this study was to examine the empirical and methodological cost-effectiveness evidence of surgical interventions for breast, colorectal, or prostate cancer. METHODS: A systematic search of seven databases including MEDLINE, EMBASE, and NHSEED, research registers, the NICE Web site and conference proceedings was conducted in April 2012. Study quality was assessed in terms of meeting essential, preferred and UK NICE specific requirements for economic evaluations. RESULTS: The seventeen (breast = 3, colorectal = 7, prostate = 7) included studies covered a broad range of settings (nine European; eight non-European) and six were published over 10 years ago. The populations, interventions and comparators were generally well defined. Very few studies were informed by literature reviews and few used synthesized clinical evidence. Although the interventions had potential differential effects on recurrence and mortality rates, some studies used relatively short time horizons. Univariate sensitivity analyses were reported in all studies but less than a third characterized all uncertainty with a probabilistic sensitivity analysis. Although a third of studies incorporated patients' health-related quality of life data, only four studies used social tariff values. CONCLUSIONS: There is a dearth of recent robust evidence describing the cost-effectiveness of surgical interventions in the management of breast, colorectal and prostate cancers. Many of the recent publications did not satisfy essential methodological requirements such as using clinical evidence informed by a systematic review and synthesis. Given the ratio of potential benefit and harms associated with cancer surgery and the volume of resources consumed by these, there is an urgent need to increase economic evaluations of these technologies.

The cost-effectiveness of different chemotherapy strategies for patients with poor prognosis advanced colorectal cancer (MRC FOCUS).

OBJECTIVES: To assess the value for money of alternative chemotherapy strategies for managing advanced colorectal cancer using irinotecan or oxaliplatin, either in sequence or in combination with fluorouracil. METHODS: A cost-effectiveness model was developed using data from the U.K. fluorouracil, oxaliplatin, and CPT11 (irinotecan)--use and sequencing (FOCUS) trial. The analysis adopted the perspective of the U.K. National Health Service. Input parameters were derived using a system of risk equations (for probabilities), count data regression models (for resource use), and generalized linear models (for utilities). Parameter estimates were obtained using Markov chain Monte Carlo methods, propagating the simulation values through the state-transition model to characterize appropriately the joint distributions of expected cost, survival and quality-adjusted life years for each treatment strategy. An acceptability frontier was used to represent the probability that the optimal option is cost-effective at different values of the cost-effectiveness threshold. RESULTS: The base-case analysis used drug unit costs provided by a typical English hospital. First-line doublet therapy combination therapy fluorouracil (5FU) plus irinotecan was the most cost-effective strategy at standard thresholds, with an incremental cost-effectiveness ratio (ICER) of £14,877 (pound sterling) compared with first-line 5FU until treatment failure followed by single agent irinotecan. Other strategies were all subject to extended dominance. A sensitivity analysis using published drug (list) prices found the most cost-effective strategy would be first-line fluorouracil until failure followed by 5FU plus irinotecan (ICER: £19,753). CONCLUSIONS: The combination of 5FU and irinotecan (whether used first or second line) appears to be more cost-effective than the single agent sequential therapies used in the FOCUS trial, or 5FU plus oxaliplatin.

Endovascular versus open repair of abdominal aortic aneurysm.

BACKGROUND: Few data are available on the long-term outcome of endovascular repair of abdominal aortic aneurysm as compared with open repair. METHODS: From 1999 through 2004 at 37 hospitals in the United Kingdom, we randomly assigned 1252 patients with large abdominal aortic aneurysms (> or = 5.5 cm in diameter) to undergo either endovascular or open repair; 626 patients were assigned to each group. Patients were followed for rates of death, graft-related complications, reinterventions, and resource use until the end of 2009. Logistic regression and Cox regression were used to compare outcomes in the two groups. RESULTS: The 30-day operative mortality was 1.8% in the endovascular-repair group and 4.3% in the open-repair group (adjusted odds ratio for endovascular repair as compared with open repair, 0.39; 95% confidence interval [CI], 0.18 to 0.87; P=0.02). The endovascular-repair group had an early benefit with respect to aneurysm-related mortality, but the benefit was lost by the end of the study, at least partially because of fatal endograft ruptures (adjusted hazard ratio, 0.92; 95% CI, 0.57 to 1.49; P=0.73). By the end of follow-up, there was no significant difference between the two groups in the rate of death from any cause (adjusted hazard ratio, 1.03; 95% CI, 0.86 to 1.23; P=0.72). The rates of graft-related complications and reinterventions were higher with endovascular repair, and new complications occurred up to 8 years after randomization, contributing to higher overall costs. CONCLUSIONS: In this large, randomized trial, endovascular repair of abdominal aortic aneurysm was associated with a significantly lower operative mortality than open surgical repair. However, no differences were seen in total mortality or aneurysm-related mortality in the long term. Endovascular repair was associated with increased rates of graft-related complications and reinterventions and was more costly. (Current Controlled Trials number, ISRCTN55703451.)

An economic model for the prevention of MRSA infections after surgery: non-glycopeptide or glycopeptide antibiotic prophylaxis?

AIM: Surgical site infection is commonly caused by Staphylococcus aureus. The multiresistant strains (MRSA) are resistant to most antibiotic prophylaxis regimens. Our aim was to explore whether there is a threshold of MRSA prevalence at which switching to routine glycopeptide-based antibiotic prophylaxis becomes cost-effective. METHODS: An indicative model was designed to explore the cost-effectiveness of vancomycin, cephalosporin or a combination, in patients undergoing primary hip arthroplasty. RESULTS: If the MRSA infection rate is equal to or above 0.25% and the rate of other infections with cephalosporin prophylaxis is equal to or above 0.2%, use of the combination antibiotic prophylaxis is optimal. DISCUSSION: Modelling the cost-effectiveness of interventions for MRSA prevention is complex due to uncertainty around resistance and effectiveness of glycopeptides. CONCLUSIONS: The indicative model provides a framework for evaluation. More work is needed to understand the impact of antibiotic resistance over time in these currently effective antibiotics.

Laparoscopic fundoplication compared with medical management for gastro-oesophageal reflux disease: cost effectiveness study.

OBJECTIVE: To describe the long term costs, health benefits, and cost effectiveness of laparoscopic surgery compared with those of continued medical management for patients with gastro-oesophageal reflux disease (GORD). DESIGN: We estimated resource use and costs for the first year on the basis of data from the REFLUX trial. A Markov model was used to extrapolate cost and health benefit over a lifetime using data collected in the REFLUX trial and other sources. PARTICIPANTS: The model compared laparoscopic surgery and continued proton pump inhibitors in male patients aged 45 and stable on GORD medication. INTERVENTION: Laparoscopic surgery versus continued medical management. MAIN OUTCOME MEASURES: We estimated quality adjusted life years and GORD related costs to the health service over a lifetime. Sensitivity analyses considered other plausible scenarios, in particular size and duration of treatment effect and the GORD symptoms of patients in whom surgery is unsuccessful. Main results The base case model indicated that surgery is likely to be considered cost effective on average with an incremental cost effectiveness ratio of pound2648 (euro3110; US$4385) per quality adjusted life year and that the probability that surgery is cost effective is 0.94 at a threshold incremental cost effectiveness ratio of pound20 000. The results were sensitive to some assumptions within the extrapolation modelling. CONCLUSION: Surgery seems to be more cost effective on average than medical management in many of the scenarios examined in this study. Surgery might not be cost effective if the treatment effect does not persist over the long term, if patients who return to medical management have poor health related quality of life, or if proton pump inhibitors were cheaper. Further follow-up of patients from the REFLUX trial may be valuable. TRIAL REGISTRATION: ISRCTN15517081.

The cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia.

OBJECTIVE: To assess the cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia, as implementation at the local health centre level has yet to be undertaken in many resource-limited countries despite recommendations in recent updated World Health Organization (WHO) guidelines. DESIGN: A probabilistic decision analytical model of HIV/AIDS progression in children based on the CD4 cell percentage (CD4%) was populated with data from the placebo-controlled Children with HIV Antibiotic Prophylaxis trial that had reported a 43% reduction in mortality with cotrimoxazole prophylaxis in HIV-infected children aged 1-14 years. METHODS: Unit costs (US$ in 2006) were measured at University Teaching Hospital, Lusaka. Cost-effectiveness expressed as cost per life-year saved, cost per quality adjusted life-year (QALY) saved, cost per disability adjusted life-year (DALY) averted was calculated across a number of different scenarios at tertiary and primary healthcare centres. RESULTS: : Cotrimoxazole prophylaxis was associated with incremental cost-effectiveness ratios (ICERs) of US$72 per life-year saved, US$94 per QALY saved and US$53 per DALY averted, i.e. substantially less than a cost-effectiveness threshold of US$1019 per outcome (gross domestic product per capita, Zambia 2006). ICERs of US$5 or less per outcome demonstrate that cotrimoxazole prophylaxis is even more cost-effective at the local healthcare level. The intervention remained cost-effective in all sensitivity analyses including routine haematological and CD4% monitoring, varying starting age, AIDS status, cotrimoxazole formulation, efficacy duration and discount rates. CONCLUSION: Cotrimoxazole prophylaxis in HIV-infected children is an inexpensive low technology intervention that is highly cost-effective in Zambia, strongly supporting the adoption of WHO guidelines into essential healthcare packages in low-income countries.

Quality of life, resource consumption and costs of spinal cord stimulation versus conventional medical management in neuropathic pain patients with failed back surgery syndrome (PROCESS trial).

BACKGROUND: Chronic back and leg pain conditions result in patients' loss of function, reduced quality of life and increased costs to the society. AIMS: To assess health-related quality of life (HRQoL) and cost implications of spinal cord stimulation plus non-surgical conventional medical management (SCS group) versus non-surgical conventional medical management alone (CMM group) in the management of neuropathic pain in patients with failed back surgery syndrome. METHODS: A total of 100 patients were randomised to either the SCS or CMM group. Healthcare resource consumption data relating to screening, the use of the implantable generator in SCS patients, hospital stay, and drug and non-drug pain-related treatment were collected prospectively. Resource consumption was costed using UK and Canadian 2005-2006 national figures. HRQoL was assessed using the EuroQol-5D (EQ-5D) questionnaire. Costs and outcomes were assessed for each patient over their first 6-months of the trial. RESULTS: The 6-month mean total healthcare cost in the SCS group (CAN$19,486; 12,653 euros) was significantly higher than in the CMM group (CAN$3994; 2594 euros), with a mean adjusted difference of CAN$15,395 (9997 euros) (p<0.001). However, the gain in HRQoL with SCS over the same period of time was markedly greater in the SCS group, with a mean EQ-5D score difference of 0.25 [p<0.001] and 0.21 [p<0.001], respectively at 3- and 6-months after adjusting for baseline variables. CONCLUSIONS: The addition of SCS to CMM in patients with neuropathic leg and back pain results in higher costs to health systems but also generates important improvements in patients' EQ-5D over the same period.

Identifying research priorities: the value of information associated with repeat screening for age-related macular degeneration.

The authors report an analysis that was developed as part of a pilot study examining the use of decision analysis and value-of-information methods to inform research prioritization decisions for the UK health care system. This analysis was conducted to inform decision makers whether additional research on screening for age-related macular degeneration (AMD) would be worthwhile and to demonstrate the benefits and feasibility of using such analytic methods to inform policy decision within the time-lines demanded by existing procedures. A probabilistic decision model was developed to establish the cost-effectiveness of a policy of repeat screening for AMD using the Amsler grid followed by treatment with photodynamic therapy (PDT) compared with 2 alternatives: PDT without screening (self-referral) and no screening or treatment. Screening for AMD appears to be cost-effective on the basis of existing evidence; however, the decision to implement a policy of screening is somewhat uncertain, with a probability that screening is cost-effective of 0.87 and 0.72 for the 20/40 and 20/80 models, respectively, at a threshold of 30,000 pounds per quality-adjusted life-year. The expected value of perfect information (EVPI) associated with this decision is substantial (6.9 million pounds for the 20/40 model and 14.5 million pounds for the 20/80 model), with a sizeable EVPI associated with the effect of PDT on quality of life. The analysis demonstrates that EVPI analysis can be implemented in a timely fashion to inform the type of research prioritization decisions faced by any health care system. This case study also illustrates the need to account for any structural uncertainties appropriately.

Assessing generalisability by location in trial-based cost-effectiveness analysis: the use of multilevel models.

Cost-effectiveness analysis (CEA) in health care is increasingly conducted alongside multicentre and multinational randomised controlled clinical trials (RCTs). The increased use of stochastic CEA is designed to account for between-patient sampling variability in cost-effectiveness data assuming that observations are independently distributed. However, between-location variability in cost-effectiveness may result if there is a hierarchical structure in the data; that is, if there is correlation in costs and outcomes between patients recruited in particular locations. This may be expected in multi-location trials given that centres and countries often differ in factors such as clinical practice, patient case-mix and the unit costs of delivering health care. A failure to acknowledge this feature may lead to misleading conclusions in a trial-based economic study. Multilevel modelling (MLM) is an analytical framework that can be used to handle hierarchical cost-effectiveness data. Using data from a recently conducted economic analysis, this paper shows how multilevel modelling can be used to obtain (a) more appropriate estimates of the population average incremental cost-effectiveness and associated standard errors compared to standard stochastic CEA; and (b) location-specific estimates of incremental cost-effectiveness which can be used to explore appropriately the variability between centres/countries of the cost-effectiveness results.

Estimating mean QALYs in trial-based cost-effectiveness analysis: the importance of controlling for baseline utility.

In trial-based cost-effectiveness analysis baseline mean utility values are invariably imbalanced between treatment arms. A patient's baseline utility is likely to be highly correlated with their quality-adjusted life-years (QALYs) over the follow-up period, not least because it typically contributes to the QALY calculation. Therefore, imbalance in baseline utility needs to be accounted for in the estimation of mean differential QALYs, and failure to control for this imbalance can result in a misleading incremental cost-effectiveness ratio. This paper discusses the approaches that have been used in the cost-effectiveness literature to estimate absolute and differential mean QALYs alongside randomised trials, and illustrates the implications of baseline mean utility imbalance for QALY calculation. Using data from a recently conducted trial-based cost-effectiveness study and a micro-simulation exercise, the relative performance of alternative estimators is compared, showing that widely used methods to calculate differential QALYs provide incorrect results in the presence of baseline mean utility imbalance regardless of whether these differences are formally statistically significant. It is demonstrated that multiple regression methods can be usefully applied to generate appropriate estimates of differential mean QALYs and an associated measure of sampling variability, while controlling for differences in baseline mean utility between treatment arms in the trial.

A cost-utility analysis of tension-free vaginal tape versus colposuspension for primary urodynamic stress incontinence.

OBJECTIVE: To assess the cost effectiveness of tension-free vaginal tape compared with open Burch colposuspension as a primary treatment for urodynamic stress incontinence. DESIGN: Cost-utility analysis alongside a multicentre randomised comparative trial. SETTING: Gynaecology or Urology departments in 14 centres in the UK and Ireland, including University-associated teaching hospitals and district general hospitals. POPULATION: Women with urodynamic stress incontinence. Exclusion criteria were: (1) detrusor overactivity; (2) major voiding problems; (3) prolapse; (4) previous surgery for incontinence or prolapse. METHODS: Resource use data were collected on all 344 patients in the trial, including length of hospital stay, time in theatre and management of complications; resource use was costed using UK unit costs at 1999-2000 prices. MAIN OUTCOME MEASURES: Health outcomes were expressed in terms of quality-adjusted life years (QALYs) between baseline and six months follow up, based on women's responses to the EQ-5D health questionnaire. RESULTS: Tension-free vaginal tape resulted in a mean cost saving of pound 243 (95% CI pound 341 to pound 201) compared with colposuspension. Differential mean QALYs per patient (tension-free vaginal tape - colposuspension) was 0.01 (95% CI -0.01 to 0.03). The probability of tension-free vaginal tape being, on average, less costly than colposuspension, was 100%, and the probability of tension-free vaginal tape being more cost effective than colposuspension was 94.6% if the decision-maker was willing to pay pound 30,000 per additional QALY. CONCLUSIONS: The results from this trial suggest that, over a post-operative period of six months, tension-free vaginal tape is a cost effective alternative to colposuspension. The results will need to be reassessed on the basis of longer follow up.

A survey of women's preferences regarding alternative surgical treatments for menorrhagia.

BACKGROUND: Menorrhagia represents a major health burden to a large number of women in the UK. A range of medical and surgical treatments is now available for the condition, but each has its own advantages and limitations. METHODS: A postal survey was undertaken of women with apparently uncomplicated menorrhagia referred to one of two NHS hospitals. The aim was to elicit women's preferences for the characteristics of surgical treatment and, specifically, to assess how they traded-off the characteristics of hysterectomy and minimal access surgery. RESULTS: A total of 221 women returned their questionnaire and were included in the study (59% of those sent out). The characteristics most frequently rated as 'very important' were getting back to usual activities as soon as possible (57%), experiencing the least pain and discomfort (46%), spending a short time in hospital (46%) and stopping periods for good (43%). The single characteristic most frequently rated as the most important by women was stopping periods for good (28%). Similar proportions of women preferred abdominal hysterectomy (43%) and endometrial resection (41%) when these were described to them. When asked to think about specific treatments of which they were aware, strong positive (43%) and negative (42%) preferences were indicated. Women's main information source was their general practitioner (70%), but only 44% considered themselves well-informed about menorrhagia and its treatment. CONCLUSIONS: Many women referred to hospital with menorrhagia have conflicting objectives for treatment, feel under-informed about therapies and have not formed treatment preferences. It is important to develop well-structured and accessible sources of information for women and methods to elicit their treatment preferences, and to evaluate the impact of such tools on treatment selection and outcomes.