Simon McNamara’s journal round-up for 8th April 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.

National Institute for Health and Care Excellence, social values and healthcare priority setting. Journal of the Royal Society of Medicine [PubMed] Published 2nd April 2019

As is traditional, this week’s round-up starts with an imaginary birthday party. After much effort, we have finally managed to light the twenty candles, have agreed our approach to the distribution of the cake, and are waiting in anticipation of the entrance of the birthday “quasi-autonomous non-governmental body”. The door opens. You clear your throat. Here we go…

Happy Birthday to you,

Happy Birthday to you,

Happy Birthday dear National Institute for Health and Care Excellence,

Happy Birthday to you.

NICE smiles happily. It is no longer a teenager. It has made it to 20 – despite its parents challenging it a few times (cough, Cancer Drug Fund, cough). After the candles have been blown out, someone at the back shouts: “Speech! Speech!”. NICE coughs, thanks everyone politely, and (admittedly slight strangely) takes the opportunity to announce that they are revising their “Social Value Judgements” paper – a document that outlines the principles they use to develop guidance. They then proceed to circle the room, proudly handing out draft copies of the new document- “The principles that guide the development of NICE guidance and standards” (PDF). They look excited. Your fellow guests start to read.

“Surely not?”, “What the … ?”, “Why?” – they don’t seem pleased. You jump into the document. All of this is about process. Where are all the bits about justice, and inequalities, and bioethics, and the rest? “Why have you taken out loads of the good stuff?” you ask. “This is too vague, too procedural”. Your disappointment is obvious to those in the room.

Your phone pings – it’s your favourite WhatsApp group. One of the other guests has already started drafting a “critical friend” paper in the corner of the room. They want to know if you want to be involved. “I’m in”, you respond, “This is important, we need to make sure NICE knows what we think”. Your phone pings again. Another guest is in: “I want to be involved, this matters. Also, this is exactly the kind of paper that will get picked up by the AHE blog. If we are lucky, we might even be the first paper in one of their journal round-ups”. You pause, think, and respond hopefully: “Fingers crossed”.

I don’t know if NICE had an actual birthday party – if they did I certainly wasn’t invited. I also highly doubt that the authors of this week’s first paper, or indeed any paper, had the AHE blog in mind when writing. What I do know, is that the first article is indeed a “critical friend” paper which outlines the authors’ concerns with NICE’s proposal to “revise” (read: delete) their social value judgements guidance. This paper is relatively short, so if you are interested in these changes I suggest you read it, rather than relying on my imaginary birthday party version of their concerns.

I am highly sympathetic to the views expressed in this paper. The existing “social value judgements” document is excellent, and (to me at least) seems to be the gold standard in setting the values by which an HTA body should develop guidance. Reducing this down to solely procedural elements seems unnecessary, and potentially harmful if the other core values are forgotten, or deprioritised.

As I reflect on this paper, I can’t help think of the old adage: “If it ain’t broke, don’t fix it”. NICE – this ain’t broke.

Measuring survival benefit in health technology assessment in the presence of nonproportional hazards. Value in Health Published 22nd March 2019

Dear HTA bodies that don’t routinely look for violations of proportional hazards in oncology data: 2005 called, they want their methods back.

Seriously though, it’s 2019. Things have moved on. If a new drug has a different mode of action to its comparator, is given for a different duration, or has differing levels of treatment effect in different population subgroups, there are good reasons to think that the trial data for that drug might violate proportional hazards. So why not look? It’s easy enough, and could change the way you think about both the costs and the benefits of that medicine.

If you haven’t worked in oncology before, there is a good chance you are currently asking yourself two questions: “what does proportional hazards mean?” and “why does it matter?”. In massively simplified terms, when we say the hazards in a trial are “proportional” we mean that the treatment effect of the new intervention (typically on survival) is constant over time. If a treatment takes some time to work (e.g. immunotherapies), or is given for only a few weeks before being stopped (e.g. some chemotherapies), there are good reasons to think that the treatment effect of that intervention may vary over time. If this is the case, there will be a violation of proportional hazards (they will be “nonproportional”).

If you are an HTA body, this is important for at least three reasons. First, if hazards are non-proportional, this can mean that the average hazard ratio (treatment effect) from the trial is a poor representation of what is likely to happen beyond the trial period – a big issue if you are extrapolating data in an economic model. Second, if hazards are non-proportional, this can mean that the median survival benefit from the trial is a poor representation of the mean benefit (e.g. in the case of a curve with a “big tail”). If you don’t account for this, and rely on medians (as some HTA bodies do), this can result in your evaluation under-estimating, or over-estimating, the true benefits and costs of the medicine. Third, most approaches to including indirect comparison in economic models rely on proportionality so, if this doesn’t hold, your model might be a poor representation of reality. Given these issues, it makes sense that HTA bodies should be looking for violations in proportional hazards when evaluating oncology data.

In this week’s second paper, the authors review the way different HTA bodies approach the issue of non-proportionality in their methods guides, and in a sample of their appraisals. Of the HTA bodies considered, they find that only NICE (UK), CADTH (Canada), and PBAC (Australia) recommend testing for proportional hazards. Notably, the authors report that the Transparency Committee (France), IQWiG (Germany), and TLV (Sweden) don’t recommend testing for proportionality. Interestingly, despite these recommendations, the authors find that solely the majority of NICE appraisals they reviewed included these tests, and that only 20% of the PBAC appraisals and 8% of the CADTH appraisals did. This suggests that the vast majority of oncology drug evaluations do not include consideration of non-proportionality – a big concern given the issues outlined above.

I liked this paper, although I was a bit shocked at the results. If you work for an HTA body that doesn’t recommend testing for non-proportionality, or doesn’t enforce their existing recommendations, I suggest you think very carefully about this issue – particularly if you rely on the extrapolation of survival curves in your assessments. If you aren’t looking for violations of proportional hazards, there is a good chance that you aren’t reflecting the true costs and benefits of many medicines in your evaluations. So, why not look for them?

The challenge of antimicrobial resistance: what economics can contribute. Science Published 5th April 2019

Health Economics doesn’t normally make it into Science (the journal). If it does, it probably means the paper is an important one. This one certainly is.

Antimicrobial resistance (AMR) is scary – really scary. One source cited in this paper predicts that by 2050, 10 million people a year will die due to AMR. I don’t know about you, but I find this pretty worrying (how’s that for a bit of British understatement?). Given these predicted consequences, you would think that there would be quite a lot of work from economists on this issue. Well, there isn’t. According to this article, there are only 55 papers on EconLit that “broadly relate” to AMR.

This paper contributes to this literature in two important ways. First, it is a call to arms to economists to do more work on AMR. If there are only 55 papers on this topic, this suggests we are only scratching the surface of the issue and could do more as a field contribute to helping solve the problem. Second, it neatly demonstrates how economics could be applied to the problem of AMR – including analysis of both the supply side (not enough new antibiotics being developed) and demand side (too much antibiotic use) of the problem.

In the main body of the paper, the authors draw parallels between the economics of AMR and the economics of climate change: both are global instances of the ‘tragedy of the commons’, both are subject to significant uncertainty about the future, and both are highly sensitive to inter-temporal discounting. They then go on to suggest that many of the ideas developed in the context of climate change could be applied to AMR – including the potential for use of antibiotic prescribing quotas (analogous to carbon quotas) and taxation of antibiotic prescriptions (analogous to the idea of a carbon tax). There are many other ideas in the paper, and if you are interested in these I suggest you take the time to read it in full.

I think this is an important paper and one that has made me think more about the economics of both AMR and, inadvertently, climate change. With both issues, I can’t help but think we might be sleepwalking into a world where we have royally screwed over future generations because we didn’t take the actions we needed to take. If economists can help stop these things happening, we need to act. If we don’t, what will you say in 2050 when you turn on the news and see that 10 million people are dying from AMR each year? That is, assuming you aren’t one of those who has died as a result. Scary stuff indeed.


Simon McNamara’s journal round-up for 21st January 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.

Assessing capability in economic evaluation: a life course approach? The European Journal of Health Economics [PubMed] Published 8th January 2019

If you have spent any time on social media in the last week there is a good chance that you will have seen the hashtag #10yearchallenge. This hashtag is typically accompanied by two photos of the poster; one recent, and one from 10 years ago. Whilst the minority of these posts suggest that the elixir of permanent youth has been discovered and is being hidden away by a select group of people, the majority show clear signs of ageing. As time passes, we change. Our skin becomes wrinkled, our hair may become grey, and we may become heavier. What these pictures don’t show, is how we change internally – and I don’t mean biologically. As we become older, and we experience life, so the things we think are important change. Our souls become wrinkled, and our minds become heavier.

The first paper in this week’s round-up is founded on this premise, albeit grounded in the measurement of capability well-being across the life course, rather than a hashtag. The capabilities approach is grounded in the normative judgement that the desirability of policy outcomes should be evaluated by what Sen called the ‘capabilities’ they provide – “the functionings, or the capabilities to function” they give people, where functionings for a person are defined as “the various things that he or she manages to do or be in leading a good life” (Sen, 1993). The author (Joanna Coast) appeals to her, and others’, work on the family of ICECAP measures (capability measures), in order to argue that the capabilities we value changes across the stage of life we are experiencing. For example, she notes that the development work for the ICECAP-A (adults) resulted in the choice of an ‘achievement’ attribute in that instrument, whilst for ICECAP-O (older people) an alternative ‘role’ attribute was used – with the achievement attribute primarily linked to having the ability to make progress in life, and the role attribute linked to having the ability to do things that make you feel valued. Similarly, she notes that the attributes that emerged from development work on the ICECAP-SCM (supportive care – a term for the end of life) are different to those from ICECAP-A (adults), with dignity coming to the forefront as a valued attribute towards the end of life. The author then goes on to suggest that it would be normatively desirable to capture how the capabilities we value changes over the life-course, suggests this could be done with a range of different measures, and highlights a number of problems associated with this (e.g. when does a life-stage start and finish?).

You should read this paper. It is only four pages long and definitely worth your time. If you have spent enough time on social media to know what the #10yearchallenge is, then you definitely have time to read it. I think this is a really interesting topic and a great paper. It has certainly got me thinking more about capabilities, and I will be keeping an eye out for future papers on this in future.

Future directions in valuing benefits for estimating QALYs: is time up for the EQ-5D? Value in Health Published 17th January 2019

If EQ-5D were a person, I think I would be giving it a good hug right now. Every time my turn to write this round-up comes up there seems to be a new article criticising it, pointing out potential flaws in the way it has been valued, or proposing a new alternative. If it could speak, I imagine it would tell us it is doing its best – perhaps with a small tear in its eye. It has done what it can to evolve, it has tried to change, but as we approach its 30th birthday, and exciting new instruments are under development, the authors of the second paper in this week’s round-up question – “Is time up for the EQ-5D?”

If you are interested in the valuation of outcomes, you should probably read this paper. It is a really neat summary of recent developments in the assessment and valuation of the benefits of healthcare, and gives a good indication of where the field may be headed. Before jumping into reading the paper, it is worth dwelling on its title. Note that the authors have used the term “valuing benefits for estimating QALYs” and not “valuing health states for estimating QALYs”. This is telling, and reflects the growing interest in measuring, and valuing, the benefits of healthcare based upon a broader conception of well-being, rather than simply health as represented by the EQ-5D. It is this issue that rests at the heart of the paper, and is probably the biggest threat to the long-term domination of EQ-5D. If it wasn’t designed to capture the things we are now interested in, then why not modify it further, or go back to the drawing board and start again?

I am not going to attempt to cover all the points made in the paper, as I can’t do it justice in this blog; but in summary, the authors review a number of ways this could be done, outline recent developments in the way the subsequent instrument could be valued, and detail the potential advantages, disadvantages, and challenges of moving to a new instrument. Ultimately, the authors conclude that the future of the valuation of outcomes – be that with EQ-5D or something else, depends upon a number of judgements, including whether non-health factors are considered to be relevant when valuing the benefits of healthcare. If they are then EQ-5D isn’t fit for purpose, and we need a new instrument. Whilst the paper doesn’t provide a definitive answer to the question “Is Time Up for the EQ-5D?”, the fact that NICE, the EuroQol group, two of the authors of this paper, and a whole host of others, are currently collaborating on a new measure, which captures both health and non-health outcomes, indicates that EQ-5D may well be nearing the end of its dominance. I look forward to seeing how this work progresses over the next few years.

The association between economic uncertainty and suicide in the short-run. Social Science and Medicine [PubMed] [RePEc] Published 24th November 2018

As I write this, the United Kingdom is 10 weeks away from the date we are due to leave the European Union, and we are still uncertain about how, and potentially even whether, we will finally leave. The uncertainty created by Brexit covers both economic and social spheres, and impacts many of those in the United Kingdom, and many beyond who have ties to us. I am afraid the next paper isn’t a cheery one, but given this situation, it is a timely one.

In the final paper in this round-up, the authors explore the link between economic uncertainty and short-term suicide rates. This is done by linking the UK EPU index of economic uncertainty – an index generated based upon the articles published in 650 UK newspapers – to the daily suicide rates in England and Wales between 2001 and 2015. The authors find evidence of an increase in suicide rates on the days on which the EPU index was higher, and also of a lagged effect on the day after a spike in the index. Over the course of a year, this effect means a one standard deviation increase in the EPU is expected to lead to 11 additional deaths in that year. In comparison to the number of deaths per year from cardiovascular disease, and cancer, this effect is relatively modest, but is nevertheless concerning given the nature of the way in which these people are dying.

I am not going to pretend I enjoyed reading this paper. Technically it is good, and it is an interesting paper, but the topic was just a bit too dark and too relevant to our current situation. Whilst reading I couldn’t help but wonder whether I am going to be reading a similar paper linking Brexit uncertainty to suicide at some point in the future. Fingers crossed this isn’t the case.


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?