Simon McNamara’s journal round-up for 1st October 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.

A review of NICE appraisals of pharmaceuticals 2000-2016 found variation in establishing comparative clinical effectiveness. Journal of Clinical Epidemiology [PubMed] Published 17th September 2018

The first paper in this week’s round-up is on the topic on single arm studies; specifically, the way in which the comparative effectiveness of medicines granted a marketing authorisation on the basis of single arm studies have been evaluated in NICE appraisals. If you are interested in comparative effectiveness, single arm studies are difficult to deal with. If you don’t have a control arm to refer to, how do you know what the impact of the intervention is? If you don’t know how effective the intervention is, how can you say whether it is cost-effective?

In this paper, the authors conduct a review into the way this problem has been dealt with during NICE appraisals. They do this by searching through the 489 NICE technology appraisals conducted between 2010 and 2016. The search identified 22 relevant appraisals (4% of the total). The most commonly used way of estimating comparative effectiveness (19 of 22 appraisals) was simulation of a control arm using external data – be that from observational study or a randomised trial. Of these,14 of the appraisals featured naïve comparison across studies, with no attempt made to adjust for potential differences between population groups. The three appraisals that didn’t use external data were reliant upon the use of expert opinion, or the assumption that non-responders in the intervention single-arm study could be used as a proxy for those who would receive the comparator intervention.

Interestingly, the authors find little difference between the proportion of medicines reliant on non-RCT data being approved by NICE (83%), compared to those with RCT data (86%), however; the likelihood of receiving an “optimised” (aka subgroup) approval was substantially higher for medicines with solely non-RCT data (41% vs 19%). These findings demonstrate that NICE do accept models based on single-arm studies – even if more than 75% of the comparative effectiveness estimates these models were based on were reliant upon naïve indirect comparisons, or other less robust methods.

The paper concludes by noting that single-arm studies are becoming more common (50% of the appraisals identified were conducted in 2015-2016), and suggesting that HTA and regulatory bodies should work together, to develop guidance on how to evaluate comparative effectiveness based on single-arm studies.

I thought this paper was great, and it made me reflect on a couple of things. Firstly, the fact that NICE completed such a high volume of appraisals (489) between 2010 and 2016 is extremely impressive – well done NICE. Secondly, should the EMA, or EUnetHTA, play a larger role in providing estimates of comparative effectiveness for single arm studies? Whilst different countries may reasonably make different value judgements about different health outcomes, comparative effectiveness is – at least in theory – a matter of fact, rather than values, so can’t we assess it centrally?

A QALY loss is a QALY loss is a QALY loss: a note on independence of loss aversion from health states. The European Journal of Health Economics [PubMed] Published 18th September 2018

If I told you that you would receive £10 in return for doing some work for me, and then I only paid you £5, how annoyed would you be? What about if I told you I would give you £10 but then gave you £15? How delighted would you be? If you are economically rational then these two impacts (annoyance vs being delighted) should be symmetrical; but, if you are a human, your annoyance in the first scenario would likely outweigh the delight you would experience in the second. This is the basic idea behind Kahneman and Tversky’s seminal work on “loss aversion” – we dislike changes we perceive as losses more than we like equivalent changes we perceive as gains. The second paper in this week’s roundup explores loss aversion in the context of health. Application of loss aversion in health is a really interesting idea, because it calls into question the idea that people value all QALYs equally – perhaps QALYs perceived as losses are valued more highly than QALYs perceived as gains.

In the introduction of this paper, the authors note that existing evidence suggests loss aversion is present for duration of life, and for quality of life, but note that nobody has explored whether loss aversion remains constant if the two elements change together – simply put, when it comes to loss aversion is “a QALY loss a QALY loss a QALY loss”? The authors test this idea via a choice experiment fielded in a sample of 111 Dutch students. In this experiment, the loss aversion of each participant was independently elicited for four EQ-5D-5L health states – ranging from perfect health down to a health state utility value of 0.46.

As you might have guessed from the title of the paper, the authors found that, at the aggregate level, loss aversion was not significantly different between the four health states – albeit with some variation at the individual level. For each health state, perceived losses were weighted around two times as highly as perceived gains.

I enjoyed this paper, and it prompted me to think about the consequences of loss-aversion for health economics more generally. Do health related decision makers treat the outcomes associated with a new technology as a reference-point, and so feel loss aversion when considering not funding it? From a normative perspective, should we accept asymmetry in the valuation of health? Is this simply a behavioural quirk that we should over-ride in our analyses, or should we be conforming to it and granting differential weight to outcomes depending upon whether the recipient perceives it as a gain or a loss?

Advanced therapy medicinal products and health technology assessment principles and practices for value-based and sustainable healthcare. The European Journal of Health Economics [PubMed] Published 18th September 2018

The final paper in this week’s roundup is on “Advanced Therapy Medicinal Products” (ATMPs). According to the European Union Regulation 1394/2007, an ATMP is a medicine which is either (1) a gene therapy, (2) a somatic-cell therapy, (3) a tissue-engineered therapy, or (4) a combination of these approaches. I don’t pretend to understand the nuances of how these medicines work, but in simple terms ATMPs aim to replace, or regenerate, human cells, tissues and organs in order to treat ill health. Whilst ATMPs are thought to have great potential in improving health and providing long-term survival gains, they present a number of challenges for Health Technology Assessment (HTA) bodies.

This paper details a meeting of a panel of experts from the UK, Germany, France and Sweden, who were tasked with identifying and discussing these challenges. The experts identified three key challenges; (1) uncertainty of long-term benefit, and subsequently cost-effectiveness, (2) discount rates, and (3) capturing the broader “value” of these therapies – including the incremental value associated with potentially curative therapies. These three challenges stem from the fact that at the point of HTA, ATMPs are likely to have immature data and the uncertain prospect of long-term benefits. The experts suggest a range of solutions to these problems, including the use of outcomes-based reimbursement schemes, initiating a multi-disciplinary forum to consider different approaches to discounting, and further research into elements of “value” not captured by current HTA processes.

Whilst there is undoubtedly merit to some of these suggestions, I couldn’t help but feel a bit uneasy about this paper due to its funder – an ATMP manufacturer. Would the authors have written this paper if they hadn’t been paid to by a company with a vested interest in changing HTA systems to suit their agenda? Whilst I don’t doubt the paper was written independently of the company, and don’t mean to cast aspersions on the authors, this does make me question how industry shapes the areas of discourse in our field – even if it doesn’t shape the specific details of that discourse.

Many of the problems raised in this paper are not unique to ATMPs, they apply equally to all interventions with the uncertain prospect of potential cure or long-term benefit (e.g. for therapies for the treatment of early stage cancer, public health interventions or immunotherapies). Science aside, funder aside, what makes ATMPs any different to these prior interventions?

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Chris Sampson’s journal round-up for 13th March 2017

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.

The effects of exercise and relaxation on health and wellbeing. Health Economics [PubMedPublished 9th Month 2017

Encouraging self-management of health sounds like a good idea, but the evidence is pretty weak. As economists, we know that something must be displaced in order to do it. This study considers the opportunity cost of time and how it might affect self-management activity and any associated benefits. Employment and education are likely to increase income and thus facilitate more expenditure on exercise. But the time cost of exercise is also likely to increase, meaning that the impact on demand is ambiguous. The study uses data from a trial of self-management support that included people with diabetes, COPD or IBS. EQ-5D, self-assessed health and the amount of time spent ‘being happy’ were all collected. Information was available for 12 different self-management activities, including ‘do exercises’ and ‘rest and relax’, and the extent to which individuals did these. Outcomes for 3,472 people at 12-month follow-up are estimated, controlling for outcomes at baseline and 6 months. The study assumes that employment and education affect health via their influence on exercise and relaxation. That seems a bit questionable and the other 10 self-management indicators could have been looked at to test this. People in full-time employment were 11 percentage points less likely to use relaxation to manage their condition, suggesting that the substitution effect on time dominates as the opportunity cost of self-management increases. Having a degree or professional qualification increased the probability of using exercise by 5 percentage points, suggesting that the income effect dominates. Those who are more likely to use either exercise or relaxation are also more likely to do the other. An interesting suggestion is that time preference might explain things here. Those with more education may prefer to exercise (as an investment) than to get the instant gratification of rest and relaxation. It’s important that policy recommendations take into consideration the fact that different groups will respond differently to incentives for self-management, at least partly due to their differing time constraints. The thing I find most interesting is the analysis of the different outcomes (something I’ve worked on). Exercise is found to improve self-assessed health, while relaxation increases happiness. Neither exercise or relaxation had a (statistically significant) effect on EQ-5D. Depending on your perspective, this either suggests that the EQ-5D is failing to identify important changes in broad health-related domains or it means that self-management does not achieve the goals (QALYs to the max) of the health service.

New findings from the time trade-off for income approach to elicit willingness to pay for a quality adjusted life year. The European Journal of Health Economics [PubMedPublished 8th March 2017

The question ‘what is a QALY worth’ could invoke any number of reactions in a health economist, from chin scratching to eye rolling. The perspective that we’re probably most familiar with in the UK is that the value of a QALY is the value of health foregone in order to achieve it (i.e. opportunity cost within the health care perspective). An alternative perspective is that the value of a QALY is the consumption value of health; how much consumption would individuals be willing to give up in order to obtain an additional QALY? This second perspective facilitates a broader societal perspective. It can tell us whether or not the budget is set at an appropriate level, while the health care perspective can only take the budget as given. This study relates mainly to decisions made with the ‘consumption value’ perspective. One approach that has been proposed is to assess willingness to pay for a QALY using a time trade-off exercise that incorporates trade-offs between length and quality of life and income. This study builds on the original work by using a multiplicative utility function to estimate willingness to pay and also bringing in prospect theory to allow for reference dependence and loss aversion. 550 participants were asked to choose between living 10 years in their current health state with their current salary or to live a reduced number of years in their current health state with a luxury income (pre-specified by the participant). Respondents were also asked to make a similar choice, but framed as a loss of income, between living 10 years at a subsistence income or fewer years with their current income. A quality of life trade-off exercise was also conducted, in which people traded reduced health and a lower income. The findings support the predictions of prospect theory. Loss aversion is found to be stronger for duration than for quality of life. Individuals were more willing to sacrifice life years to move from subsistence income to current income than to move from current income to luxury income. The results imply that quality of life and income are closer substitutes than longevity and income. That makes sense, given the all-or-nothing nature of being alive. Crucially, the findings highlight the need to better understand the shape of the underlying lifetime utility function. In all tasks, more than half of respondents were either non-traders or over-traded, indicating a negative willingness to pay. That should give pause for thought when it comes to any aggregation of the results. Willingness to pay studies often throw up more questions than answers. This one does so more than most, particularly about sources of bias in people’s responses. The authors identify plenty of opportunities for future research.

Beyond QALYs: multi-criteria based estimation of maximum willingness to pay for health technologies. The European Journal of Health Economics [PubMed] Published 3rd March 2017

Life is messy. Evaluating things in terms of a single outcome, whether that be QALYs, £££s or whatever, is necessarily simplifying and restrictive. That’s not necessarily a bad thing, but we’d do well to bear it in mind. In this paper, Erik Nord sets out a kind of cost value analysis that does away with QALYs (gasp!). The author starts by outlining some familiar criticisms of the QALY approach, such as its failure to consider the inherent value of life and people’s differing reference points. Generally, I see these as features rather than bugs, and it isn’t QALYs themselves in the crosshairs here so much as cost-per-QALY analysis. The proposed method flips current practice by putting societal preferences about fair and efficient resource allocation before attaching values to the outcomes. As such, it acknowledges the fact that society’s preferences for gains in quality of life differ from those for gains in length of life. For example, society may prefer treating the more severely ill (independent of age) but also exhibit a ‘fair innings’ preference that is related to age. Thus, quality and quantity of life are disaggregated and the QALY is no more. A set of tables is presented that can be read to assess ‘value’ in alternative scenarios, given the assumptions set out in the paper. There is merit in the approach and a lot that I like about the possibilities of its use. But for me, the whole thing was made less attractive by the way it is presented in the paper. The author touts willingness to pay – for quality of life gains and for longevity gains – as the basis for value. Anything that makes resource allocation more dependent on willingness to pay values for things without a price (health, life) is a big no-no for me. But the method doesn’t depend on that. Furthermore, as is so often the case, most of the criticisms within relate to ways of using QALYs, rather than the fundamental basis for their estimation. This only weakens the argument for an alternative. But I can think of plenty of problems with QALYs, some of which might be addressed by this alternative approach. It’s unfortunate that the paper doesn’t outline how these more fundamental problems might be addressed. There may come a day when we do away with QALYs, and we may end up doing something similar to what’s outlined here, but we need to think harder about how this alternative is really better.

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