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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Rita Faria’s journal round-up for 24th September 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.

Methodological issues in assessing the economic value of next-generation sequencing tests: many challenges and not enough solutions. Value in Health [PubMed] Published 8th August 2018

This month’s issue of Value in Health includes a themed section on assessing the value of next-generation sequencing. Next-generation sequencing is sometimes hailed as the holy grail in medicine. The promise is that our individual genome can indicate how at-risk we are for many diseases. The question is whether the information obtained by these tests is worth their costs and potentially harmful consequences on well-being and health-related quality of life. This largely remains unexplored, so I expect seeing more economic evaluations of next-generation sequencing in the future.

This paper has caught my eye given an ongoing project on cascade testing protocols for familial hypercholesterolaemia. Next-generation sequencing can be used to identify the genetic cause of familial hypercholesterolaemia, thereby identifying patients suitable to have their relatives tested for the disease. I read this paper with the hope of finding inspiration for our economic evaluation.

This thought-provoking paper discusses the challenges in conducting economic evaluations of next-generation sequencing, such as complex model structure, inclusion of upstream and downstream costs, identifying comparators, identifying costs and outcomes that are related to the test, measuring costs and outcomes, evidence synthesis, data availability and quality.

I agree with the authors that these are important challenges, and it was useful to see them explained in a systematic way. Another valuable feature of this paper is the summary of applied studies which have encountered these challenges and their approaches to overcome them. It’s encouraging to read about how other studies have dealt with complex decision problems!

I’d argue that the challenges are applicable to economic evaluations of many other interventions. For example, identifying the relevant comparators can be a challenge in the evaluations of treatments: in an evaluation of hepatitis C drugs, we compared 633 treatment sequences in 14 subgroups. I view the challenges as the issues to think about when planning an economic evaluation of any intervention: what the comparators are, the scope of the evaluation, the model conceptualisation, data sources and their statistical analysis. Therefore, I’d recommend this paper as an addition to your library about the conceptualisation of economic evaluations.

Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource. BMJ [PubMed] Published 12th September 2018

You may be puzzled at the choice of the latest Ben Goldacre and colleagues’ paper, as it does not include an economic component. This study investigates compliance with the European Commission’s requirements that all trials on the EU Clinical Trials Register post results to the registry within 12 months of completion. At first sight, the economic implications may not be obvious, but they do exist and are quite important.

Clinical trials are a large investment of resources, not only financial but also in the health of patients who accept to take part in an experiment that may impact their health adversely. Therefore, clinical trials can have a huge sunk cost in both money and health. The payoff only realises if the trial is reported. If the trial is not reported, the benefits from the investment cannot be realised. In sum, an unreported trial is clearly a cost-ineffective use of resources.

The solution is simple: ensure that trial results are reported. This way we can all benefit from the information collected by the trial. The issue is, as Goldacre and colleagues have revealed, compliance is far from perfect.

Remarkably, around half of the 7,274 studies are due to publish results. The worst offenders are non-commercial sponsors, where only 11% of trials had their results reported (compared with 68% of trials by a commercial sponsor).

The authors provide a web tool to look up unreported trials by institution. I looked up my very own University of York. It was reassuring to know that my institution has no trials due to report results. Nonetheless, many others are less compliant.

This is an exciting study on the world of clinical trials. I’d suggest that a possible next step would be to estimate the health lost and costs from failing to report trial results.

Network meta-analysis of diagnostic test accuracy studies identifies and ranks the optimal diagnostic tests and thresholds for health care policy and decision-making. Journal of Clinical Epidemiology [PubMed] Published 13th March 2018

Diagnostic tests are an emerging area of methodological development. This timely paper by Rhiannon Owen and colleagues addresses the important topic of evidence synthesis of diagnostic test accuracy studies.

Diagnostic test studies cannot be meta-analysed with the standard techniques used for treatment effectiveness. This is because there are two quantities of interest (sensitivity and specificity), which are correlated, and vary depending on the test threshold (that is, the value at which we say the test result is positive or negative).

Owen and colleagues propose a new approach to synthesising diagnostic test accuracy studies using network meta-analysis methodology. This innovative method allows for comparing multiple tests, evaluated at various test threshold values.

I cannot comment on the method itself as evidence synthesis is not my area of expertise. My interest comes from my experience in the economic evaluation of diagnostic tests, where we often wish to combine evidence from various studies.

With this in mind, I recommend having a look at the NIHR Complex Reviews Support Unit website for more handy tools and the latest research on methods for evidence synthesis. For example, the CRSU has a web tool for meta-analysis of diagnostic tests and a web tool to conduct network meta-analysis for those of us who are not evidence synthesis experts. Providing web tools is a brilliant way of helping analysts using these methods so, hopefully, we’ll see greater use of evidence synthesis in the future.

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Thesis Thursday: Angela Devine

On the third Thursday of every month, we speak to a recent graduate about their thesis and their studies. This month’s guest is Dr Angela Devine who has a PhD from The Open University. If you would like to suggest a candidate for an upcoming Thesis Thursday, get in touch.

Title
The economics of vivax malaria treatment
Supervisors
Yoel Lubell, Ric Price, Ricardo Aguas, Shunmay Yeung
Repository link
https://thesiscommons.org/zsc6x/

What is vivax malaria and what are some of the key challenges that it presents for health economists?

One infectious bite from a mosquito carrying vivax malaria can lead to multiple episodes of malaria due to dormant liver parasites called hypnozoites. We can’t tell the difference between these relapse infections and new infections, which means that it’s challenging to model. Unlike falciparum malaria, which frequently results in severe outcomes and deaths, vivax malaria doesn’t often result in direct mortality. Instead, it likely causes indirect mortality through the malnutrition and anaemia that are caused by repeated malaria episodes. Unfortunately, the evidence of this is limited.

To prevent future relapses, patients need to be given a drug to treat the liver parasites (radical cure) in addition to treating the blood stage treatment. The only drug that is currently licensed for radical cure, primaquine, can cause potentially life-threatening haemolysis in individuals who have a genetic disorder called glucose-6-phosphate-dehydrogenase (G6PD) deficiency. While some countries are so concerned about haemolytic events that primaquine isn’t used at all, other settings prescribe primaquine to everyone. The evidence on the risk of primaquine-induced haemolysis and death is sparse, and expert opinion on this matter is fiercely divided.

How did you go about collecting the data needed for your study?

Not much has been done previously on vivax malaria costs, which meant that a lot of my work involved generating cost data. I started by analysing some fairly old data that my supervisors had from a study on treatment-seeking behaviour in Papua, Indonesia. The cost of illness study indicated that household costs were similar for both vivax and falciparum malaria in 2006. I also collected provider and patient-level cost data alongside a multi-country clinical trial on vivax malaria treatment. I wasn’t able to travel to the some of the study sites (e.g. Afghanistan) to collect the provider costs, so I had to create worksheets for local trial staff to fill out. It was an iterative process, particularly with the first site in Indonesia, but it got faster and easier to do each time. I’m very thankful that the local teams were enthusiastic about this work and patient with my many questions and requests.

What is the economic burden of vivax malaria and who bears the cost?

A lot of vivax malaria episodes occur in remote areas where access to care is limited. The highest incidence of the disease is in children, particularly those under the age of five. This often means that someone will need to take time off from usual activities, such as farming, attending school, or household chores, to care for the sick. I estimated the global economic burden to be US$330 million. These estimates don’t include mortality, malnutrition or anaemia. Since we know that repeated episodes can have a profound impact on a household’s income, I included productivity losses for those who were ill and their carers. We also know that malaria causes educational losses, so I included these productivity costs for children as well as adults to try to capture some of those losses. In total, productivity losses accounted for US$263 million, nearly 80% of the total costs. Since many who are affected by this disease aren’t paid for their work, I used one GDP per capita per day for every day lost to illness or caretaking. Other methods of valuing these losses would have a substantial impact on the total costs. While there’s a considerable amount of uncertainty around some of the numbers I used and assumptions that I made, my hope is that by identifying the issues, we will be able to generate the data needed for better estimates in the future.

What methods did you use to evaluate the cost-effectiveness of new treatment strategies?

Asia-Pacific malaria control programs stated that the cost of G6PD screening was an obstacle to its widespread use. My research addressed those concerns through a decision tree model in R that weighed up the costs, risks and benefits of screening using newly developed G6PD rapid diagnostic tests (RDTs) before prescribing primaquine. I wanted to make this work as relevant to policymakers as possible, so I did two separate comparisons. First I compared this strategy to not using primaquine, then I compared it to prescribing primaquine to everyone without screening. While this strayed from typical economic evaluation methods, it seemed unlikely that a setting where primaquine isn’t prescribed due to fear of haemolysis would switch to prescribing primaquine to everyone without screening, or that a setting where primaquine is prescribed to everyone would stop using it altogether.

As G6PD deficiency is X-linked, the risk of haemolysis varies by gender, so results need to be stratified by gender. The prevalence and severity of G6PD deficiency and the latency period and number of relapses for vivax malaria varies geographically. While I wanted to have more than one setting to explore how these might impact the results, four comparisons was already a lot of information to present. Instead, I used R-shiny with my model to create an interactive website where people can see how changes in the baseline model parameters impact the results. My goal was to provide a tool that policymakers could use to help make decisions about treatment strategies in their settings. This also provides an opportunity to explore the impact of parameter values that may be seen as contentious.

What are some of the issues you encountered in working with policymakers to ensure that cost-effective treatments become more widely used?

One issue is that patients, especially those who can afford to do so, seek treatment in the private sector, which is harder to control. Encouragingly, the follow-up survey in Papua, Indonesia indicated that changing treatment policy in the public sector also had an impact on how private sector providers diagnosed and treated malaria. As someone keen to influence policy, I benefited a lot from meetings with malaria control program officials from the Asia Pacific. These provided insights on the challenges that countries are facing. For example, the work I did on G6PD screening was aimed at addressing the cost issue that kept coming up in these meetings. Unfortunately, I’m not aware of settings where they have begun to routinely use G6PD RDTs. There are additional barriers, like getting the tests licensed so that malaria control programs can purchase them with a subsidy from The Global Fund. Another issue that I hadn’t fully appreciated before beginning my PhD is that funding for diseases like malaria is often siloed for specific purposes by the various donors. This can make it more challenging to ensure that countries are getting the best possible value for the money that is spent. There’s also been a lot of debate recently about what willingness to pay threshold should be used in poorly resourced settings. This is a debate that we need to have, but it also makes it more challenging to decide which treatments should be considered to be cost-effective.