Modeling Covariate-Adjusted Survival for Economic Evaluations in Oncology.

BACKGROUND AND OBJECTIVES: In economic evaluations in oncology, adjusted survival should be generated if imbalances in prognostic/predictive factors across treatment arms are present. To date, no formal guidance has been developed regarding how such adjustments should be made. We compared various covariate-adjusted survival modeling approaches, as applied to the ENDEAVOR trial in multiple myeloma that assessed carfilzomib plus dexamethasone (Cd) versus bortezomib plus dexamethasone (Vd). METHODS: Overall survival (OS) data and baseline characteristics were used for a subgroup (bortezomib-naïve/one prior therapy). Four adjusted survival modeling approaches were compared: propensity score weighting followed by fitting a Weibull model to the two arms of the balanced data (weighted data approach); fitting a multiple Weibull regression model including prognostic/predictive covariates to the two arms to predict survival using the mean value of each covariate and using the average of patient-specific survival predictions; and applying an adjusted hazard ratio (HR) derived from a Cox proportional hazard model to the baseline risk estimated for Vd. RESULTS: The mean OS estimated by the weighted data approach was 6.85 years (95% confidence interval [CI] 4.62-10.70) for Cd, 4.68 years (95% CI 3.46-6.74) for Vd, and 2.17 years (95% CI 0.18-5.06) for the difference. Although other approaches estimated similar differences, using the mean value of covariates appeared to yield skewed survival estimates (mean OS was 7.65 years for Cd and 5.40 years for Vd), using the average of individual predictions had limited external validity (implausible long-term OS predictions with > 10% of the Vd population alive after 30 years), and using the adjusted HR approach overestimated uncertainty (difference in mean OS was 2.03, 95% CI - 0.17 to 6.19). CONCLUSIONS: Adjusted survival modeling based on weighted or matched data approaches provides a flexible and robust method to correct for covariate imbalances in economic evaluations. The conclusions of our study may be generalizable to other settings. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01568866 (ENDEAVOR trial).

Which factors enhance positive drug reimbursement recommendation in Scotland? A retrospective analysis 2006-2013.

OBJECTIVES: To identify the factors that influence the Scottish Medicines Consortium (SMC) in deciding whether to accept pharmaceutical technologies for use within the Scottish health care system. METHODS: A database of SMC submissions between 2006 and 2013 was created, containing a range of clinical, economic, and other factors extracted from published health technology assessment reports. A binomial outcome variable was used, defined as the decision to "accept for use" or "not recommend" a technology. Univariate and multivariate analyses were conducted to assess the impact by means of odds ratios (ORs) of the submitted evidence on the recommendation decision. RESULTS: Out of 463 applications, 265 were accepted for use (57%) and 198 (43%) were not recommended for use within National Health Service Scotland. Univariate analyses showed that 13 variables significantly affected the SMC decision. Of these 13 variables, 7 variables were shown to have a meaningful impact in the multivariate analysis. Four of these concerned the outcome of cost-effectiveness analyses; the fact that a submission was supported by a cost-minimization analysis was the strongest positive variable (OR = 10.30) and a submission showing a product not being cost-effective (i.e., incremental cost-effectiveness ratio above £30,000/quality-adjusted life-year gained) was the strongest negative predictor (OR = 0.47). The other variables concerned whether the submission was related to a product indicated for a nervous system disease (OR = 0.41), whether it was indicated for nonchronic use (OR = 1.66), and whether the submission was performed by a big company (OR = 2.83). CONCLUSIONS: This study demonstrated that the outcome of cost-effectiveness analyses is an important factor affecting the SMC's reimbursement recommendation decision.

Efficacy, tolerability, and safety of aripiprazole once-monthly versus other long-acting injectable antipsychotic therapies in the maintenance treatment of schizophrenia: a mixed treatment comparison of double-blind randomized clinical trials.

BACKGROUND: Treatment with long-acting injectable (LAI) antipsychotic medication is an important element of relapse prevention in schizophrenia. Recently, the intramuscular once-monthly formulation of aripiprazole received marketing approval in Europe and the United States for schizophrenia. OBJECTIVE: This study aimed to compare aripiprazole once-monthly with other LAI antipsychotics in terms of efficacy, tolerability, and safety. DATA SOURCES: A systematic literature review was conducted to identify relevant double-blind randomized clinical trials of LAIs conducted in the maintenance treatment of schizophrenia. MEDLINE, MEDLINE In-Process, Embase, the Cochrane Library, PsycINFO, conference proceedings, clinical trial registries, and the reference lists of key review articles were searched. The literature search covered studies dating from January 2002 to May 2013. STUDY SELECTION: Studies were required to have ≥24 weeks of follow-up. Patients had to be stable at randomization. Studies were not eligible for inclusion if efficacy of acute and maintenance phase treatment was not reported separately. Six trials were identified (0.5% of initially identified studies), allowing comparisons of aripiprazole once-monthly, risperidone LAI, paliperidone palmitate, olanzapine pamoate, haloperidol depot, and placebo. DATA EXTRACTION: Data extracted included study details, study duration, the total number of patients in each treatment arm, efficacy, tolerability, and safety outcomes. The efficacy outcome contained the number of patients that experienced a relapse, tolerability outcomes included the number of patients that discontinued treatment due to treatment-related adverse events (AEs), and that discontinued treatment due to reasons other than AEs (e.g., loss to follow-up). Safety outcomes included the incidence of clinically relevant weight gain and extrapyramidal symptoms. DATA SYNTHESIS: Data were analyzed by applying a mixed treatment comparison competing risks model (efficacy) and using binary models (safety). There was no statistically significant difference between any study outcome, including the risk of relapse, the risk of discontinuations, and safety outcomes. CONCLUSIONS: Aripiprazole once-monthly is similarly efficacious to other LAIs with relatively low rates of discontinuation due to AEs and due to reasons other than AEs than other LAIs.

Time trends and forecasts of body mass index from repeated cross-sectional data: a different approach.

In this paper, we report a case study on a technical generalization of the Lee-Carter model, originally developed to project mortality, to forecast body mass index (BMI, kg/m2). We present the method on an annually repeated cross-sectional data set, the Dutch Health Survey, covering years between 1981 and 2008. We applied generalized additive models for location, scale and shape semi-parametric regression models to estimate the probability distribution of BMI for each combination of age, gender and year assuming that BMI follows a Box-Cox power exponential distribution. We modelled and extrapolated the distribution parameters as a function of age and calendar time using the Lee-Carter model. The projected parameters defined future BMI distributions from which we derived the prevalence of normal weight, overweight and obesity. Our analysis showed that important changes occurred not only in the location and scale of the BMI distribution but also in the shape of it. The BMI distribution became flatter and more shifted to the right. Assuming that past trends in the distribution of BMI will continue in the future, we predicted a stable or slow increase in the prevalence of overweight until 2020 among men and women. We conclude that our adaptation of the Lee-Carter model provides an insightful and flexible way of forecasting BMI and that ignoring changes in the shape of the BMI distribution would likely result in biased forecasts.

Modeling and forecasting health expectancy: theoretical framework and application.

Life expectancy continues to grow in most Western countries; however, a major remaining question is whether longer life expectancy will be associated with more or fewer life years spent with poor health. Therefore, complementing forecasts of life expectancy with forecasts of health expectancies is useful. To forecast health expectancy, an extension of the stochastic extrapolative models developed for forecasting total life expectancy could be applied, but instead of projecting total mortality and using regular life tables, one could project transition probabilities between health states simultaneously and use multistate life table methods. In this article, we present a theoretical framework for a multistate life table model in which the transition probabilities depend on age and calendar time. The goal of our study is to describe a model that projects transition probabilities by the Lee-Carter method, and to illustrate how it can be used to forecast future health expectancy with prediction intervals around the estimates. We applied the method to data on the Dutch population aged 55 and older, and projected transition probabilities until 2030 to obtain forecasts of life expectancy, disability-free life expectancy, and probability of compression of disability.

Forecasting lifetime and aggregate long-term care spending: accounting for changing disability patterns.

OBJECTIVE: The impact population aging exerts on future levels of long-term care (LTC) spending is an urgent topic in which few studies have accounted for disability trends. We forecast individual lifetime and population aggregate annual LTC spending for the Dutch 55+ population to 2030 accounting for changing disability patterns. METHODS: Three levels of (dis)ability were distinguished: none, mild, and severe. Two-part models were used to estimate LTC spending as a function of age, sex, and disability status. A multistate life table model was used to forecast age-specific prevalence of disability and life expectancy (LE) in each disability state. Finally, 2-part model estimates and multistate projections were combined to obtain forecasts of LTC expenditures. RESULTS: LE is expected to increase, whereas life years in severe disability remain constant, resulting in a relative compression of severe disability. Mild disability life years increase, especially for women. Lifetime homecare spending--mainly determined by mild disability--increases, whereas institutional spending remains fairly constant due to stable LE with severe disability. Lifetime LTC expenditures, largely determined by institutional spending, are thus hardly influenced by increasing LE. Aggregate spending for the 55+ population is expected to rise by 56.0% in the period of 2007-2030. CONCLUSIONS: Longevity gains accompanied by a compression of severe disability will not seriously increase lifetime spending. The growth of the elderly cohort, however, will considerably increase aggregate spending. Stimulating a compression of disability is among the main solutions to alleviate the consequences of longevity gains and population aging to growth of LTC spending.

Mortality risk associated with disability: a population-based record linkage study.

OBJECTIVES: We assessed the association between mortality and disability and quantified the effect of disability-associated risk factors. METHODS: We linked data from cross-sectional health surveys in the Netherlands to the population registry to create a large data set comprising baseline covariates and an indicator of death. We used Cox regression models to estimate the hazard ratio of disability on mortality. RESULTS: Among men, the unadjusted hazard ratio for activities of daily living, mobility, or mild disability defined by the Organization for Economic Co-operation and Development at age 55 years was 7.85 (95% confidence interval [CI] = 4.36, 14.13), 5.21 (95% CI = 3.19, 8.51), and 1.87 (95% CI = 1.58, 2.22), respectively. People with disability in activities of daily living and mobility had a 10-year shorter life expectancy than nondisabled people had, of which 6 years could be explained by differences in lifestyle, sociodemographics, and major chronic diseases. CONCLUSIONS: Disabled people face a higher mortality risk than nondisabled people do. Although the difference can be explained by diseases and other risk factors for those with mild disability, we cannot rule out that more severe disabilities have an independent effect on mortality.

Life expectancy and life expectancy with disability of normal weight, overweight, and obese smokers and nonsmokers in Europe.

The goal of this study was to estimate life expectancy (LE) and LE with disability (LwD) among normal weight, overweight, and obese smokers and nonsmokers in Western Europe. Data from four waves (1998-2001) of the European Community Household Panel (ECHP) were used; a standardized multipurpose annual longitudinal survey. Self-reported health and socioeconomic information was collected repeatedly using uniform questionnaires for 66,331 individuals in nine countries. Health status was measured in terms of disability in daily activities. Multistate Markov (MSM) models were applied to obtain hazard ratios (HRs) and age-specific transition rates according to BMI and smoking status. Multistate life tables were computed using the predicted transition probabilities to estimate LE and LwD. Significant associations were observed between disability incidence and BMI (HR = 1.15 for overweight, HR = 1.64 for obese, compared to normal weight). The risk of mortality was negatively associated with overweight status among disabled (HR = 0.77). Overweight people had higher LE than people with normal-weight and obesity. Among women, overweight and obese nonsmokers expect 3.6 and 6.1 more years of LwD than normal weight persons, respectively. In contrast, daily smokers expect lower LE but a similar LwD. The same patterns were observed among people with high education and those with low education. To conclude, daily smoking is associated with mortality more than with disability, whereas obesity is associated with disability more than with mortality. The findings suggest that further tobacco control would contribute to increasing LE, while tackling the obesity epidemic is necessary to prevent an expansion of disability.

Cost-effectiveness of a chemoprophylactic intervention with single dose rifampicin in contacts of new leprosy patients.

BACKGROUND: With 249,007 new leprosy patients detected globally in 2008, it remains necessary to develop new and effective interventions to interrupt the transmission of M. leprae. We assessed the economic benefits of single dose rifampicin (SDR) for contacts as chemoprophylactic intervention in the control of leprosy. METHODS: We conducted a single centre, double blind, cluster randomised, placebo controlled trial in northwest Bangladesh between 2002 and 2007, including 21,711 close contacts of 1,037 patients with newly diagnosed leprosy. We gave a single dose of rifampicin or placebo to close contacts, with follow-up for four years. The main outcome measure was the development of clinical leprosy. We assessed the cost effectiveness by calculating the incremental cost effectiveness ratio (ICER) between the standard multidrug therapy (MDT) program with the additional chemoprophylaxis intervention versus the standard MDT program only. The ICER was expressed in US dollars per prevented leprosy case. FINDINGS: Chemoprophylaxis with SDR for preventing leprosy among contacts of leprosy patients is cost-effective at all contact levels and thereby a cost-effective prevention strategy. In total, $6,009 incremental cost was invested and 38 incremental leprosy cases were prevented, resulting in an ICER of $158 per one additional prevented leprosy case. It was the most cost-effective in neighbours of neighbours and social contacts (ICER $214), slightly less cost-effective in next door neighbours (ICER $497) and least cost-effective among household contacts (ICER $856). CONCLUSION: Chemoprophylaxis with single dose rifampicin given to contacts of newly diagnosed leprosy patients is a cost-effective intervention strategy. Implementation studies are necessary to establish whether this intervention is acceptable and feasible in other leprosy endemic areas of the world.