Cost effectiveness of tyrosine kinase inhibitor therapy in metastatic gastrointestinal stromal tumors

Abstract

Background:

Tyrosine kinase inhibitors (TKIs) such as imatinib mesylate have revolutionized the treatment of primary unresectable and/or metastatic gastrointestinal stromal tumors (GISTs), providing durable disease control and extended survival. Although most patients eventually progress on therapy, dose escalation has been shown to benefit some patients. Sunitinib, a multitargeted kinase inhibitor is effective against imatinib-resistant or intolerant GIST patients. Although the cost of TKI therapy in GIST is high, no other effective systemic treatment options exist.

Objective:

Review pharmacoeconomic studies to determine the cost effectiveness (CE) of 1st- and 2nd-line TKI therapies in GIST.

Methods:

A literature review using Medline and PubMed databases was conducted to identify published economic analyses of TKI therapy in GIST. Key results from these studies were analyzed.

Results:

Six pharmacoeconomic studies were identified, including three analyses of 1st-line imatinib and three analyses of 2nd-line sunitinib. These studies employed various time horizons and discount rates and modeled CE from a number of different perspectives. Most of the pharmacoeconomic studies reviewed used survival as their efficacy endpoint, projecting outcomes beyond available data to model CE. Analyses of 2nd-line sunitinib using survival additionally faced the challenge of adjusting for the effect of placebo crossover to active treatment in the pivotal phase III study. Most studies used Markov techniques with a range of transition probabilities.

Conclusions:

Published pharmacoeconomic studies of 1st- and 2nd-line TKI therapy for advanced GIST employ various time horizons, discount rates, and different CE models. Consequently, these differences make comparisons between studies difficult. Studies of 1st-line imatinib concluded that imatinib was cost effective in advanced, metastatic GIST. Likewise, based on data reviewed here, 2nd-line sunitinib appears to be cost effective in patients with advanced GIST who are intolerant/resistant to imatinib. Key limitations of this review included inconsistency among the studies evaluated with regard to methodologies, countries of origination (currency and healthcare systems), and patient demographics.     

COMPENSATORY RESTORATION IN A RANDOM UTILITY MODEL OF RECREATION DEMAND

Natural Resource Damage Assessment cases often call for compensation in non‐monetary or restoration equivalent terms. In this article, we present an approach that uses a conventional economic model, a travel cost random utility model of site choice, to determine compensatory restoration equivalents for hypothetical beach closures on the Gulf Coast of Texas. Our focus is on closures of beaches on the Padre Island National Seashore and compensation for day‐trip users. We identify restoration projects that compensate for beach closures and that have good alignment in terms of compensating those who actually suffer from the closures. (JEL Q26)     

The determinants and labour market effects of lifelong learning

Despite the policy importance of lifelong learning, there is very little hard evidence from the UK on (a) who undertakes lifelong learning and why, and (b) the economic benefits of lifelong learning. This paper uses a rich longitudinal panel data set to look at key factors that determine whether someone undertakes lifelong learning and then models the effect of the different qualifications acquired via lifelong learning on individuals’ economic outcomes, namely wages and the likelihood of being employed. Those who left school with O-level qualifications or above were much more likely to undertake lifelong learning. Undertaking one episode of lifelong learning also increased the probability of undertaking more lifelong learning. We found little evidence of positive wage effects from lifelong learning. However, males who left school with only low-level qualifications do earn substantially more if they undertake a degree via lifelong learning. We also found important positive employment effects from lifelong learning.     

A simultaneous equations model of the educational process

This paper models the educational process as a system of six simultaneous equations. The endogenous variables include a student's achievement, motivation, expectations, efficacy, and perceived parents' and teachers' expectations. The model also includes forty-eight individual, home, peer, teacher, and school exogenous variables. Using a sample of over sixteen thousand twelfth grade students from the Equality of Educational Opportunity survey, we estimate the model by two-stage least squares and present the reduced form and structural form equations. We find that many educational outputs jointly determine one another. Also, the results suggest that school and teacher variables have important effects on educational outcomes.     

Fetal Iodine Deficiency and Schooling: A Replication of Field,Robles, and Torero (2009)*

Scholars have theorized that congenital health endowment is an important determinant of economic outcomes later in a person's life. Field, Robles, and Torero (2009, American Economic Journal: Applied Economics 1, 140–169) find large increases in educational attainment caused by a reduction of fetal iodine deficiency following a set of iodine supplementation programs in Tanzania. We revisit the Tanzanian iodine programs with a narrow and wide replication of the study by Field et al. We are able to exactly replicate the original results. We find, however, that the findings are sensitive to alternative specification choices and sample restrictions. We try to address some of these concerns in the wide replication; we increase the sample size fourfold, and we improve the precision of the treatment variable by incorporating new institutional and medical insights. Despite the improvements, no effect is found. We conclude that the available data do not provide sufficient power to detect a possible effect, as treatment assignment cannot be measured with sufficient precision.     

Costs and effectiveness of fingolimod versus alemtuzumab in the treatment of highly active relapsing-remitting multiple sclerosis in the UK: re-treatment,discount, and disutility

Objective: Patients with relapsing-remitting multiple sclerosis (RRMS) treated with disease modifying therapies (DMTs) who continue to experience disease activity may be considered for escalation therapies such as fingolimod, or may be considered for alemtuzumab. Previous economic modeling used Markov models; applying one alternative technique, discrete event simulation (DES) modeling, allows re-treatment and long-term adverse events (AEs) to be included in the analysis.

Methods: A DES was adapted to model relapse-triggered re-treatment with alemtuzumab and the effect of including ongoing quality-adjusted life year (QALY) decrements for AEs that extend beyond previous 1-year Markov cycles. As the price to the NHS of fingolimod in the UK is unknown, due to a confidential patient access scheme (PAS), a variety of possible discounts were tested. The interaction of re-treatment assumptions for alemtuzumab with the possible discounts for fingolimod was tested to determine which DMT resulted in lower lifetime costs. The lifetime QALY results were derived from modeled treatment effect and short- and long-term AEs.

Results: Most permutations of fingolimod PAS discount and alemtuzumab re-treatment rate resulted in fingolimod being less costly than alemtuzumab. As the percentage of patients who are re-treated with alemtuzumab due to experiencing a relapse approaches 100% of those who relapse whilst on treatment, the discount required for fingolimod to be less costly drops below 5%. Consideration of treatment effect alone found alemtuzumab generated 0.2 more QALYs/patient; the inclusion of AEs up to a duration of 1 year reduced this advantage to only 0.14 QALYs/patient. Modeling AEs with a lifetime QALY decrement found that both DMTs generated very similar QALYs with the difference only 0.04 QALYs/patient.

Conclusions: When the model captured alemtuzumab re-treatment and long-term AE decrements, it was found that fingolimod is cost-effective compared to alemtuzumab, assuming application of only a modest level of confidential PAS discount.     

Medication adherence and discontinuation of long-acting injectable versus oral antipsychotics in patients with schizophrenia or bipolar disorder

Aims: To examine medication adherence and discontinuation in two separate groups of patients with schizophrenia or bipolar disorder (BD), who began receiving a long-acting injectable antipsychotic (LAI) versus those who changed to a different oral antipsychotic monotherapy.

Materials and methods: The Truven Health Analytics MarketScan Multi-State Medicaid claims database was used to identify patients with schizophrenia; Truven Health Analytics MarketScan Commercial and Medicaid claims databases were used to identify patients with BD. The analyses included adult patients (≥18 years) who either began receiving an LAI (no prior LAI therapy) or changed to a different oral antipsychotic (monotherapy). The first day of initiating an LAI or changing to a new oral antipsychotic was the index date. Linear and Cox regression models were conducted to estimate medication adherence (proportion of days covered [PDC]) and time to medication discontinuation (continuous medication gap ≥60 days), respectively. Models adjusted for patient demographic and clinical characteristics, baseline medication use, and baseline ED or hospitalizations.

Results: Patients with schizophrenia (N?=?5638) who began receiving LAIs had better medication adherence (5% higher adjusted mean adherence) during the 1 year post-index period and were 20% less likely to discontinue their medication during the entire follow-up period than patients who changed to a different oral antipsychotic monotherapy, adjusting for differences between LAI users and oral users. Similarly, patients with BD (N?=?11,344) who began receiving LAIs also had 5% better medication adherence and were 19% less likely to discontinue their medication than those using oral antipsychotics.

Limitations: Clinical differences unmeasurable in this database may have been responsible for the choice of LAI versus oral antipsychotics, and these differences may be responsible for some of the adherence advantages observed.

Conclusions: This real-world study suggests that patients with schizophrenia or BD who began receiving LAIs had better medication adherence and lower discontinuation risk than those who changed to a different oral antipsychotic monotherapy.     

Modelling the dynamics of Bitcoin and Litecoin: GARCH versus stochastic volatility models

We examine and compare a large number of generalized autoregressive conditional heteroskedastic (GARCH) and stochastic volatility (SV) models using series of Bitcoin and Litecoin price returns to assess the model fit for dynamics of these cryptocurrency price returns series. The various models examined include the standard GARCH(1,1) and SV with an AR(1) log-volatility process, as well as more flexible models with jumps, volatility in mean, leverage effects, t-distributed and moving average innovations. We report that the best model for Bitcoin is SV-t while it is GARCH-t for Litecoin. Overall, the t-class of models performs better than other classes for both cryptocurrencies. For Bitcoin, the SV models consistently outperform the GARCH models and the same holds true for Litecoin in most cases. Finally, the comparison of GARCH models with GARCH-GJR models reveals that the leverage effect is not significant for cryptocurrencies, suggesting that these do not behave like stock prices.     

Potential unrecognised costs of clopidogrel pretreatment in acute coronary syndrome

Abstract

Objective: To examine adherence in clinical practice to the American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations of observing a 5-day waiting period after clopidogrel administration before undergoing coronary artery bypass graft (CABG) surgery and to examine the costs of waiting.

Methods: This retrospective study used a nationwide inpatient database (Solucient ACTracker) to identify patients who were admitted for acute coronary syndrome (ACS), and who had same-stay CABG. Cost of additional days of stay was estimated using regression analysis.

Results: The recommended 5-day waiting was adhered to in 16.9% (n=3,809) of patients. The percentage of patients with ACS undergoing CABG surgery on day 0 was 14.6%. Adherence to the waiting was higher for teaching and rural hospitals; and in female and elderly patients and urgent admissions.

Conclusions: The recommended 5-day waiting for CABG surgery after clopidogrel treatment is poorly adhered to in clinical practice. This study was unable to determine specific reasons for the low adherence; however, there may be a compromise between the clinically urgent need for revascularisation and increased risk of bleeding, as well as economic costs associated with waiting. The cost of an additional hospital day in this group of patients was approximately £1,400 per day or £7,000 for 5 days. Thus, a full 5-day wait would have a significant economic impact on hospital costs.     

Cost-effectiveness analysis of intra-articular injections of a high molecular weight bioengineered hyaluronic acid for the treatment of osteoarthritis knee pain

Objective:

To determine the cost-effectiveness of bioengineered hyaluronic acid (BioHA, 1% sodium hyaluronate) intra-articular injections in treating osteoarthritis knee pain in poor responders to conventional care (CC) including non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics.

Methods:

Two decision analytic models compared BioHA treatment with either continuation of patient’s baseline CC with no assumption of disease progression (Model 1), or CC including escalating care costs due to disease progression (NSAIDs and analgesics, corticosteroid injections, and surgery; Model 2). Analyses were based on patients who received two courses of 3-weekly intra-articular BioHA (26-week FLEXX Trial?+?26-week Extension Study). BioHA group costs included fees for physician assessment and injection regimen, plus half of CC costs. Cost-effectiveness ratios were expressed as averages and incremental costs per QALY. One-way sensitivity analyses used the 95% confidence interval (CI) of QALYs gained in BioHA-treated patients, and ±20% of BioHA treatment and CC costs. Probabilistic sensitivity analyses were performed for Model 2.

Results:

For 214 BioHA patients, the average utility gain was 0.163 QALYs (95% CI?=??0.162 to 0.488) over 52 weeks. Model 1 treatment costs were $3469 and $4562 for the BioHA and CC groups, respectively; sensitivity analyses showed BioHA to be the dominant treatment strategy, except when at the lower end of the 95% CI. Model 2 annual treatment costs per QALY gained were $1446 and $516 for the BioHA and CC groups, respectively. Using CC as baseline strategy, the incremental cost-effectiveness ratio (ICER) of BioHA was $38,741/QALY gained, and was sensitive to response rates in either the BioHA or CC groups.

Conclusion:

BioHA is less costly and more effective than CC with NSAIDs and analgesics, and is the dominant treatment strategy. Compared with escalating CC, the $38,741/QALY ICER of BioHA remains within the $50,000 per QALY willingness-to-pay threshold to adopt a new technology.     

REVEALED POLITICAL POWER

When is a polity biased? Consider an “outsider” who observes policy data but observes neither citizens’ preferences nor the underlying distribution of political power. He views political power as if it were derived from wealth‐weighted voting, where the weights determine the wealth bias. Positive weights favor the rich whereas negative ones favor the poor. We show that any policy data is rationalized by any wealth‐weighted system. However, policy and polling observations together imply explicit bounds on the set of rationalizing biases. Accumulated data narrows this band. The inferential model is consistent with models of political competition for campaign contributions.     

Economic burden and healthcare utilization associated with castration-resistant prostate cancer in a commercial and Medicare Advantage US patient population

Objective: Prostate cancer is a leading cause of cancer death in men in the US. Castration-resistant prostate cancer (CRPC) is an advanced form of the disease and has a poor prognosis and limited treatment options. The objective of this study was to identify patients with CRPC from a medical claims database, and determine the prostate cancer-related economic burden and healthcare utilization of these patients.

Methods: This was a retrospective study using claims and enrollment information from a large US database linkable to laboratory data. Male patients aged 40 or older who were diagnosed with prostate cancer and received surgical or medical castration between July 1, 2001 and December 1, 2007 were considered for study inclusion. Patients with CRPC were initially identified based on at least two increases in prostrate-specific antigen (PSA) values. Due to the small number of patients with available PSA results data, logistic regression modeling using characteristics of patients with known CRPC was used to identify a larger set of patients with likely CRPC. Per-patient per-month healthcare utilization and costs were determined using medical and pharmacy claims data.

Results: The final sample of patients with likely CRPC as determined by regression modeling included 349 patients with known CRPC identified from the database on the basis of PSA results and an additional 2391 with likely CRPC. Within this final sample of 2740 CRPC patients, there was a per-patient per-month average of 1.43 prostate cancer-related ambulatory visits, 0.04 prostate cancer-related inpatient stays, and 0.01 prostate cancer-related ER visits. Average per-patient per-month prostate cancer-related costs were $1152 (SD = $2073) for ambulatory visits, $559 (SD = $2383) for inpatient stays, $72 (SD = $229) for pharmacy costs, and $1 (SD = $14) for ER visits. Total per-patient per-month prostate cancer-related costs were on average $1799 (SD = $3505), and these costs comprised about half of the all-cause healthcare costs for these patients.

Conclusions: CRPC is a costly disease, with ambulatory visits and inpatient care accounting for a substantial proportion of the economic burden. Limitations related to the use of retrospective claims data should be considered when interpreting these results.     

COHERENCY AND COMPLETENESS OF STRUCTURAL MODELS CONTAINING A DUMMY ENDOGENOUS VARIABLE*

Let y be a vector of endogenous variables and let w be a vector of covariates, parameters, and errors or unobservables that together are assumed to determine y. A structural model y=H(y, w) is complete and coherent if it has a well‐defined reduced form, meaning that for any value of w there exists a unique value for y. Coherence and completeness simplifies identification and is required for many estimators and many model applications. Incoherency or incompleteness can arise in models with multiple decision makers, such as games, or when the decision making of individuals is either incorrectly or incompletely specified. This article provides necessary and sufficient conditions for the coherence and completeness of simultaneous equation systems where one equation is a binomial response. Examples are dummy endogenous regressor models, regime switching regressions, treatment response models, sample selection models, endogenous choice systems, and determining if a pair of binary choices are substitutes or complements.     

Examining and interpreting responsiveness of the Diabetes Medication Satisfaction measure

Abstract

Objective: Treatment satisfaction (TS) is an important patient reported outcome (PRO) in diabetes as it is correlated with outcomes necessary for optimal treatment (e.g., compliance, self-management behaviour). The objective of this study was to examine the responsiveness of the DiabMedSat, a disease-specific PRO measure, assessing Overall, Burden, Efficacy and Symptom TS.

Methods: The DiabMedSat was included in an open label, observational study of the safety and efficacy of biphasic insulin aspart 30 (NovoMix 30) in routine practice with type 2 diabetes. Responsiveness analyses, examining both internal and external responsiveness, were conducted and minimally important differences (MID) assessed.

Results: In 18,817 patients, all TS scores significantly improved after 26 weeks of treatment (p<0.001). The effect sizes for these changes were above 0.5 indicating that the ability to detect change was moderate-to-large in size. Significant differences were found for all TS scores comparing patients who met their HbA_1c goal, who improved but did not meet goal and who did not improve (p<0.01), and for patients who experienced a minor hypoglycaemic event and those who did not (p<0.001). DiabMedSat scores were able to detect changes in patients’ own global rating of satisfaction (MID ranging from 5.3 to 11.7) and in physician-rated satisfaction with patients’ HbA_1c improvement (MID ranging from 5.3 to 10.2).

Conclusions: In the context of an observational study, the DiabMedSat has been shown to be highly responsive to change and can be considered as an acceptable PRO measure for TS in diabetes.     

Can individuals’ beliefs help us understand nonadherence to malaria test results? Evidence from rural Kenya

In malaria‐endemic countries about a quarter of test‐negative individuals take antimalarials (artemisinin‐based combination therapies [ACTs]). ACT overuse depletes scarce resources for subsidies and contributes to parasite resistance. As part of an experiment in Kenya that provided subsidies for rapid diagnostic test and/or for ACTs conditionally on being positive, we studied the association between beliefs on malaria status (prior and posterior the intervention) and decisions to get tested and to purchase ACTs. We find that prior beliefs do not explain the decision of getting tested (conditional on the price) and nonadherence to a negative test. However, test‐negative individuals who purchase ACTs report higher posterior beliefs than those who do not, consistent with a framework in which the formers revise beliefs upward, while the latters do not change or revise downward. We also do not find evidence that prior beliefs on ACT effectiveness and trust in test results play any major role in explaining testing or treatment behavior. Further research is needed to improve adherence to malaria‐negative test results.     

THE EFFECTS OF FISCAL POLICY SHOCKS IN SVAR MODELS: A GRAPHICAL MODELLING APPROACH

We apply graphical modelling (GM) theory to identify fiscal policy shocks in SVAR models of the US economy. Unlike other econometric approaches – which achieve identification by relying on potentially contentious a priori assumptions – GM is a data based tool. Our results are in line with Keynesian theoretical models, being also quantitatively similar to those obtained in the recent SVAR literature à la Blanchard and Perotti (2002) , and contrast with neoclassical real business cycle predictions. Stability checks confirm that our findings are not driven by sample selection.     

Playing the wrong game: An experimental analysis of relational complexity and strategic misrepresentation

It has been suggested that players often produce simplified and/or misspecified mental models of strategic decisions [Kreps, D., 1990. Game Theory and Economic Modeling. Oxford Univ. Press, Oxford]. We submit that the relational structure of players' preferences in a game is a source of cognitive complexity, and may be an important driver of such simplifications. We provide a classification of order structures in two-person games based on the properties of monotonicity and projectivity, and present experiments in which subjects construct representations of games of different relational complexity and subsequently play the games according to these representations. Experimental results suggest that relational complexity matters. More complex games are harder to represent, and this difficulty seems correlated with short term memory capacity. In addition, most erroneous representations are simpler than the correct ones. Finally, subjects who misrepresent the games behave consistently with such representations, suggesting that in many strategic settings individuals may act optimally on the ground of simplified and mistaken premises.