Chris Sampson’s journal round-up for 11th March 2019

Every Monday our authors provide a round-up of some of the most recently published peer reviewed articles from the field. We don’t cover everything, or even what’s most important – just a few papers that have interested the author. Visit our Resources page for links to more journals or follow the HealthEconBot. If you’d like to write one of our weekly journal round-ups, get in touch.

Identification, review, and use of health state utilities in cost-effectiveness models: an ISPOR Good Practices for Outcomes Research Task Force report. Value in Health [PubMed] Published 1st March 2019

When modellers select health state utility values to plug into their models, they often do it in an ad hoc and unsystematic way. This ISPOR Task Force report seeks to address that.

The authors discuss the process of searching, reviewing, and synthesising utility values. Searches need to use iterative techniques because evidence requirements develop as a model develops. Due to the scope of models, it may be necessary to develop multiple search strategies (for example, for different aspects of disease pathways). Searches needn’t be exhaustive, but they should be systematic and transparent. The authors provide a list of factors that should be considered in defining search criteria. In reviewing utility values, both quality and appropriateness should be considered. Quality is indicated by the precision of the evidence, the response rate, and missing data. Appropriateness relates to the extent to which the evidence being reviewed conforms to the context of the model in which it is to be used. This includes factors such as the characteristics of the study population, the measure used, value sets used, and the timing of data collection. When it comes to synthesis, the authors suggest it might not be meaningful in most cases, because of variation in methods. We can’t pool values if they aren’t (at least roughly) equivalent. Therefore, one approach is to employ strict inclusion criteria (e.g only EQ-5D, only a particular value set), but this isn’t likely to leave you with much. Meta-regression can be used to analyse more dissimilar utility values and provide insight into the impact of methodological differences. But the extent to which this can provide pooled values for a model is questionable, and the authors concede that more research is needed.

This paper can inform that future research. Not least in its attempt to specify minimum reporting standards. We have another checklist, with another acronym (SpRUCE). The idea isn’t so much that this will guide publications of systematic reviews of utility values, but rather that modellers (and model reviewers) can use it to assess whether the selection of utility values was adequate. The authors then go on to offer methodological recommendations for using utility values in cost-effectiveness models, considering issues such as modelling technique, comorbidities, adverse events, and sensitivity analysis. It’s early days, so the recommendations in this report ought to be changed as methods develop. Still, it’s a first step away from the ad hoc selection of utility values that (no doubt) drives the results of many cost-effectiveness models.

Estimating the marginal cost of a life year in Sweden’s public healthcare sector. The European Journal of Health Economics [PubMed] Published 22nd February 2019

It’s only recently that health economists have gained access to data that enables the estimation of the opportunity cost of health care expenditure on a national level; what is sometimes referred to as a supply-side threshold. We’ve seen studies in the UK, Spain, Australia, and here we have one from Sweden.

The authors use data on health care expenditure at the national (1970-2016) and regional (2003-2016) level, alongside estimates of remaining life expectancy by age and gender (1970-2016). First, they try a time series analysis, testing the nature of causality. Finding an apparently causal relationship between longevity and expenditure, the authors don’t take it any further. Instead, the results are based on a panel data analysis, employing similar methods to estimates generated in other countries. The authors propose a conceptual model to support their analysis, which distinguishes it from other studies. In particular, the authors assert that the majority of the impact of expenditure on mortality operates through morbidity, which changes how the model should be specified. The number of newly graduated nurses is used as an instrument indicative of a supply-shift at the national rather than regional level. The models control for socioeconomic and demographic factors and morbidity not amenable to health care.

The authors estimate the marginal cost of a life year by dividing health care expenditure by the expenditure elasticity of life expectancy, finding an opportunity cost of €38,812 (with a massive 95% confidence interval). Using Swedish population norms for utility values, this would translate into around €45,000/QALY.

The analysis is considered and makes plain the difficulty of estimating the marginal productivity of health care expenditure. It looks like a nail in the coffin for the idea of estimating opportunity costs using time series. For now, at least, estimates of opportunity cost will be based on variation according to geography, rather than time. In their excellent discussion, the authors are candid about the limitations of their model. Their instrument wasn’t perfect and it looks like there may have been important confounding variables that they couldn’t control for.

Frequentist and Bayesian meta‐regression of health state utilities for multiple myeloma incorporating systematic review and analysis of individual patient data. Health Economics [PubMed] Published 20th February 2019

The first paper in this round-up was about improving practice in the systematic review of health state utility values, and it indicated the need for more research on the synthesis of values. Here, we have some. In this study, the authors conduct a meta-analysis of utility values alongside an analysis of registry and clinical study data for multiple myeloma patients.

A literature search identified 13 ‘methodologically appropriate’ papers, providing 27 health state utility values. The EMMOS registry included data for 2,445 patients in 22 counties and the APEX clinical study included 669 patients, all with EQ-5D-3L data. The authors implement both a frequentist meta-regression and a Bayesian model. In both cases, the models were run including all values and then with a limited set of only EQ-5D values. These models predicted utility values based on the number of treatment classes received and the rate of stem cell transplant in the sample. The priors used in the Bayesian model were based on studies that reported general utility values for the presence of disease (rather than according to treatment).

The frequentist models showed that utility was low at diagnosis, higher at first treatment, and lower at each subsequent treatment. Stem cell transplant had a positive impact on utility values independent of the number of previous treatments. The results of the Bayesian analysis were very similar, which the authors suggest is due to weak priors. An additional Bayesian model was run with preferred data but vague priors, to assess the sensitivity of the model to the priors. At later stages of disease (for which data were more sparse), there was greater uncertainty. The authors provide predicted values from each of the five models, according to the number of treatment classes received. The models provide slightly different results, except in the case of newly diagnosed patients (where the difference was 0.001). For example, the ‘EQ-5D only’ frequentist model gave a value of 0.659 for one treatment, while the Bayesian model gave a value of 0.620.

I’m not sure that the study satisfies the recommendations outlined in the ISPOR Task Force report described above (though that would be an unfair challenge, given the timing of publication). We’re told very little about the nature of the studies that are included, so it’s difficult to judge whether they should have been combined in this way. However, the authors state that they have made their data extraction and source code available online, which means I could check that out (though, having had a look, I can’t find the material that the authors refer to, reinforcing my hatred for the shambolic ‘supplementary material’ ecosystem). The main purpose of this paper is to progress the methods used to synthesise health state utility values, and it does that well. Predictably, the future is Bayesian.

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Chris Sampson’s journal round-up for 17th December 2018

Every Monday our authors provide a round-up of some of the most recently published peer reviewed articles from the field. We don’t cover everything, or even what’s most important – just a few papers that have interested the author. Visit our Resources page for links to more journals or follow the HealthEconBot. If you’d like to write one of our weekly journal round-ups, get in touch.

Health related quality of life aspects not captured by EQ-5D-5L: results from an international survey of patients. Health Policy Published 14th December 2018

Generic preference-based measures, such as the EQ-5D, cannot capture all aspects of health-related quality of life. They’re not meant to. Rather, their purpose is to capture just enough information to be able to adequately distinguish between health states with respect to the domains deemed normatively relavent to decisionmakers. The stated aim of this paper is to determine whether people with a variety of chronic conditions believe that their experiences can be adequately represented by the EQ-5D-5L.

The authors conducted an online survey, identifying participants through 320 patient associations across 47 countries. Participants were asked to complete the EQ-5D-5L and then asked if any aspects of their illness, which had a “big impact” on their health, were not captured by the EQ-5D-5L. 1,031 people started the survey and 767 completed it. More than half were from the UK. 51% of respondents said that there was some aspect of health not captured by the EQ-5D-5L. Of them, 19% mentioned fatigue, 12% mentioned medication side effects, 9.5% mentioned co-morbid conditions, and then a bunch of others in smaller proportions.

It’s nice to know what people think, but I have a few concerns about the usefulness of this study. One of the main problems is that it doesn’t seem safe to assume that respondents interpret “big impact” as meaning “an impact that is independently important in determining your overall level of quality of life”. So, even if we accept that people judging something to be important makes it important (which I’m not sure it does), then we still can’t be sure whether what they are identifying is within the scope of what we’re trying to measure. For starters, I can see no justification for including a ‘medication side effects’ domain. There’s also some concern about selection and attrition. I’d guess that people with more complicated or less common health concerns would be more likely to start and finish a survey about more complicated or less common health concerns.

The main thing I took from this study is that half of respondents with chronic diseases thought that the EQ-5D-5L captured every single aspect of health that had a “big impact”, and that there wasn’t broad support for any other specific dimension.

Reducing drug wastage in pharmaceuticals dosed by weight or body surface areas by optimising vial sizes. Applied Health Economics and Health Policy [PubMed] Published 5th December 2018

It’s common for pharmaceuticals to be wasted. Not just those out-of-date painkillers you threw in the bin, but also the expensive stuff being used in hospitals. One of the main reasons that waste occurs is that vials are made to specific sizes and, often, dosage varies from patient to patient – according to weight, for example – and doesn’t match the vial size. Suppose that vials are available as 50mg and 80mg and that an individual requires a 60mg dose. One way to address this might be to allow for vial sharing, whereby the leftovers are given to the next patient. But that isn’t always possible. So, we might like to consider what the best combination of available vial sizes should be, given the characteristics of the population.

In this paper, the authors set out the problem mathematically. Essentially, the optimisation problem is to minimise cost across the population subject to the vial sizes. An example is presented for two drugs (pembrolizumab and cabazitaxel), simulating patients based on samples drawn from the Health Survey for England. Simplifications are applied to the examples, such as setting a constraint of 8 vials per patient and assuming that prices are linear (i.e. fixed per milligram).

Pembrolizumab is currently available in 50mg and 100mg vials, and the authors estimate current wastage to be 13.2%. The simulations show that switching the 50mg to a 70mg would cut wastage to 8.6%. Cabazitaxel is available in 60mg vials, resulting in 19.4% wastage. Introducing a 12.5mg vial would cut wastage by around two thirds. An important general finding, which should be self-evident, is that vial sizes should not be divisible by each other, as this limits the number of possible combinations.

Depending on when vial sizes are determined (e.g. pre- or post-authorisation), pharmaceutical companies might use it to increase profit margins, or health systems might use it to save costs. Regardless, wastage isn’t useful. Evidence-based manufacture is an example of one of those best ideas; the sort that is simple and seems obvious once it’s spelt out. It’s a rare opportunity to benefit patients, health care providers, and manufacturers, with no significant burden on policymakers.

Death or debt? National estimates of financial toxicity in persons with newly-diagnosed cancer. The American Journal of Medicine [PubMed] Published October 2018

If you’re British, what’s the scariest thing about an ‘Americanised’ (/Americanized) health care system? Expensive inhalers? A shortened life expectancy? My guess is that the prospect of having to add financial ruin to terminal illness looms pretty large. You should make sure your fear is evidence-based. Here’s a paper to shake in the face of anyone who doesn’t support universal health care.

The authors use data from the Health and Retirement Study from 1998-2014, which includes people over 50 years of age and includes new (self-reported) diagnoses of cancer. This was the basis for inclusion in the study, with over 9.5 million new diagnoses of cancer. Up to two years pre-diagnosis was taken as a baseline. The data set also includes information on participants’ assets and debts, allowing the authors to use change in net worth as the primary outcome. Generalised linear models were used to assess various indicators of financial toxicity, including change or incurrence of consumer debt, mortgage debt, and home equity debt at two- and four-year follow-up. In addition to cancer diagnosis, various chronic comorbidities and socio-demographic variables were included in the models.

Shockingly, after two years following diagnosis, 42.4% of people had depleted their entire life’s assets. Average net worth had dropped $92,000. After four years, 38.2% were still insolvent. Women, older people, people who weren’t White, people with Medicaid, and those with worsening cancer status were among those more likely to have completely depleted their assets within two years. Having private insurance and being married had protective effects, as we might expect. There were some interesting findings associated with the 2008 financial crisis, which also seemed to be protective. And a protective effect associated with psychiatric comorbidity deserves more thought.

It’s difficult to explain away any (let alone all) of the magnitude of these findings. The analysis seems robust. But, given all other evidence available about out-of-pocket costs for cancer patients in the US, it should be shocking but not unexpected. The authors describe financial toxicity as ‘unintended’. There’s nothing unintended about this. Policymakers in the US keep deciding that they’d prefer to destroy the lives of sick people than allow for the spreading of that financial risk.

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Chris Sampson’s journal round-up for 5th November 2018

Every Monday our authors provide a round-up of some of the most recently published peer reviewed articles from the field. We don’t cover everything, or even what’s most important – just a few papers that have interested the author. Visit our Resources page for links to more journals or follow the HealthEconBot. If you’d like to write one of our weekly journal round-ups, get in touch.

Stratified treatment recommendation or one-size-fits-all? A health economic insight based on graphical exploration. The European Journal of Health Economics [PubMed] Published 29th October 2018

Health care is increasingly personalised. This creates the need to evaluate interventions for smaller and smaller subgroups as patient heterogeneity is taken into account. And this usually means we lack the statistical power to have confidence in our findings. The purpose of this paper is to consider the usefulness of a tool that hasn’t previously been employed in economic evaluation – the subpopulation treatment effect pattern plot (STEPP). STEPP works by assessing the interaction between treatments and covariates in different subgroups, which can then be presented graphically. Imagine your X-axis with the values defining the subgroups and your Y-axis showing the treatment outcome. This information can then be used to determine which subgroups exhibit positive outcomes.

This study uses data from a trial-based economic evaluation in heart failure, where patients’ 18-month all-cause mortality risk was estimated at baseline before allocation to one of three treatment strategies. For the STEPP procedure, the authors use baseline risk to define subgroups and adopt net monetary benefit at the patient level as the outcome. The study makes two comparisons (between three alternative strategies) and therefore presents two STEPP figures. The STEPP figures are used to identify subgroups, which the authors apply in a stratified cost-effectiveness analysis, estimating net benefit in each defined risk subgroup.

Interpretation of the STEPPs is a bit loose, with no hard decision rules. The authors suggest that one of the STEPPs shows no clear relationship between net benefit and baseline risk in terms of the cost-effectiveness of the intervention (care as usual vs basic support). The other STEPP shows that, on average, people with baseline risk below 0.16 have a positive net benefit from the intervention (intensive support vs basic support), while those with higher risk do not. The authors evaluate this stratification strategy against an alternative stratification strategy (based on the patient’s New York Heart Association class) and find that the STEPP-based approach is expected to be more cost-effective. So the key message seems to be that STEPP can be used as a basis for defining subgroups as cost-effectively as possible.

I’m unsure about the extent to which this is a method that deserves to have its own name, insofar as it is used in this study. I’ve seen plenty of studies present a graph with net benefit on the Y-axis and some patient characteristic on the X-axis. But my main concern is about defining subgroups on the basis of net monetary benefit rather than some patient characteristic. Is it OK to deny treatment to subgroup A because treatment costs are higher than in subgroup B, even if treatment is cost-effective for the entire population of A+B? Maybe, but I think that creates more challenges than stratification on the basis of treatment outcome.

Using post-market utilisation analysis to support medicines pricing policy: an Australian case study of aflibercept and ranibizumab use. Applied Health Economics and Health Policy [PubMed] Published 25th October 2018

The use of ranibizumab and aflibercept has been a hot topic in the UK, where NHS providers feel that they’ve been bureaucratically strong-armed into using an incredibly expensive drug to treat certain eye conditions when a cheaper and just-as-effective alternative is available. Seeing how other countries have managed prices in this context could, therefore, be valuable to the NHS and other health services internationally. This study uses data from Australia, where decisions about subsidising medicines are informed by research into how drugs are used after they come to market. Both ranibizumab (in 2007) and aflibercept (in 2012) were supported for the treatment of age-related macular degeneration. These decisions were based on clinical trials and modelling studies, which also showed that the benefit of ~6 aflibercept prescriptions equated to the benefit of ~12 ranibizumab prescriptions, justifying a higher price-per-injection for aflibercept.

In the UK and US, aflibercept attracts a higher price. The authors assume that this is because of the aforementioned trial data relating to the number of doses. However, in Australia, the same price is paid for aflibercept and ranibizumab. This is because a post-market analysis showed that, in practice, ranibizumab and aflibercept had a similar dose frequency. The purpose of this study is to see whether this is because different groups of patients are being prescribed the two drugs. If they are, then we might anticipate heterogenous treatment outcomes and thus a justification for differential pricing. Data were drawn from an administrative claims database for 208,000 Australian veterans for 2007-2017. The monthly number of aflibercept and ranibizumab prescriptions was estimated for each person, showing that total prescriptions increased steadily over the period, with aflibercept taking around half the market within a year of its approval. Ranibizumab initiators were slightly older in the post-aflibercept era but, aside from that, there were no real differences identified. When it comes to the prescription of ranibizumab or aflibercept, gender, being in residential care, remoteness of location, and co-morbidities don’t seem to be important. Dispensing rates were similar, at around 3 prescriptions during the first 90 days and around 9 prescriptions during the following 12 months.

The findings seem to support Australia’s decision to treat ranibizumab and aflibercept as substitutes at the same price. More generally, they support the idea that post-market utilisation assessments can (and perhaps should) be used as part of the health technology assessment and reimbursement process.

Do political factors influence public health expenditures? Evidence pre- and post-great recession. The European Journal of Health Economics [PubMed] Published 24th October 2018

There is mixed evidence about the importance of partisanship in public spending, and very little relating specifically to health care. I’d be worried if political factors didn’t influence public spending on health, given that that’s a definitively political issue. How the situation might be different before and after a recession is an interesting question.

The authors combined OECD data for 34 countries from 1970-2016 with the Database of Political Institutions. This allowed for the creation of variables relating to the ideology of the government and the proximity of elections. Stationary panel data models were identified as the most appropriate method for analysis of these data. A variety of political factors were included in the models, for which the authors present marginal effects. The more left-wing a government, the higher is public spending on health care, but this is only statistically significant in the period before the crisis of 2007. Before the crisis, coalition governments tended to spend more, while governments with more years in office tended to spend less. These effects also seem to disappear after 2007. Throughout the whole period, governing parties with a stronger majority tended to spend less on health care. Several of the non-political factors included in the models show the results that we would expect. GDP per capita is positively associated with health care expenditures, for example. The findings relating to the importance of political factors appear to be robust to the inclusion of other (non-political) variables and there are similar findings when the authors look at public health expenditure as a percentage of total health expenditure. In contradiction with some previous studies, proximity to elections does not appear to be important.

The most interesting finding here is that the effect of partisanship seems to have mostly disappeared – or, at least, reduced – since the crisis of 2007. Why did left-wing parties and right-wing parties converge? The authors suggest that it’s because adverse economic circumstances restrict the extent to which governments can make decisions on the basis of ideology. Though I dare say readers of this blog could come up with plenty of other (perhaps non-economic) explanations.

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