Rita Faria’s journal round-up for 22nd 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.

Economically efficient hepatitis C virus treatment prioritization improves health outcomes. Medical Decision Making [PubMed] Published 22th August 2018

Hepatitis C treatment was in the news a couple of years ago when the new direct-acting antivirals first appeared on the scene. These drugs are very effective but also incredibly expensive. This prompted a flurry of cost-effectiveness analyses and discussions of the role of affordability in cost-effectiveness (my views here).

This compelling study by Lauren Cipriano and colleagues joins the debate by comparing various strategies to prioritise patients for treatment when the budget is not enough to meet patient demand. This is a clear example of the health losses due to the opportunity cost.

The authors compare the costs and health outcomes of various prioritisation schedules in terms of the number of patients treated, the distribution by severity and age, time to treatment, impact on end-stage liver disease, QALYs, costs and net benefit.

The differences between prioritisation schedules in terms of these various outcomes were remarkable. Reassuringly, the optimal prioritisation schedule on the basis of net benefit (the “optimisation” schedule) was the one that achieved the most QALYs and the greatest net benefit. This was even though the cost-effectiveness threshold did not reflect the opportunity cost, as it was set at $100,000 per QALY gained.

This study is fascinating. It shows how the optimal policy depends on what we are trying to maximise. The “first come first serve” schedule treats the most patients, but it is the “optimisation” schedule that achieves the most health benefits net of the opportunity cost.

Since their purpose was not to compare treatments, the authors used a representative price depending on whether patients had progressed to cirrhosis. A future study could include a comparison between drugs, as our previous work found that there are clear differences in cost-effectiveness between treatment strategies. The more cost-effective the treatment strategies, the more patients can be treated with a given budget.

The authors made the Excel model available as supporting material, together with documentation. This is excellent practice! It disseminates the work and shows openness to independent validation. Well done!

Long-term survival and value of chimeric antigen receptor T-cell therapy for pediatric patients with relapsed or refractory leukemia. JAMA Pediatrics [PubMed] Published 8th October 2018

This fascinating study looks at the cost-effectiveness of tisagenlecleucel in the treatment of children with relapsed or refractory leukaemia compared to chemotherapy.

Tisagenlecleucel is the first chimeric antigen receptor T-cell (CAR-T) therapy. CAR-T therapy is the new kid on the block in cancer treatment. It involves modifying the patient’s own immune system cells to recognise and kill the patient’s cancer (see here for details). Such high-tech treatment comes with a hefty price tag. Tisagenlecleucel is listed at $475,000 for a one-off administration.

The key challenge was to obtain the effectiveness inputs under the chemotherapy option. This was because tisagenlecleucel has only been studied in single-arm trials and individual level data was not available to the research team. The research team selected a single-arm study on the outcomes with clofarabine monotherapy, since its patients at baseline were most similar in terms of demographics and number of prior therapies to the tisagenlecleucel study.

This study is brilliant in approaching a difficult decision problem and conducting extensive sensitivity analysis. In particular, it tests the impact of common drivers of the cost-effectiveness of potentially curative therapies in children, such as the discount rate, duration of benefit, treatment initiation, and the inclusion of future health care costs. Ideally, the sensitivity analysis should also have tested the assumption that the studies informing the effectiveness inputs for tisagenlecleucel and clofarabine monotherapy were comparable or if clofarabine monotherapy does not represent the current standard of care, although it would be difficult to parameterise.

This outstanding study highlights the challenges posed by the approval of treatments based on single-arm studies. Had individual-level data been available, an adjusted comparison may have been possible, which would improve the degree of confidence in the cost-effectiveness of tisagenlecleucel. Regulators and trial sponsors should work together to make anonymised individual level data available to bonafide researchers.

Researcher requests for inappropriate analysis and reporting: a U.S. survey of consulting biostatisticians. Annals of Internal Medicine [PubMed] Published 10th October 2018

This study reports a survey of biostatisticians on the frequency and severity of requests for inappropriate analysis and reporting. The results are stunning!

The top 3 requests in terms of severity were to falsify statistical significance to support a desired result, change data to achieve the desired outcome and remove/alter data records to better support the research hypothesis. Fortunately, this sort of requests appears to be rare.

The top 3 requests in terms of frequency seem to be not showing a plot because it does not show an effect as strong as it had been hoped; to stress only the significant findings but under-reporting non-significant ones, and report results before data have been cleaned and validated.

Given the frequency and severity of the requests, the authors recommend that researchers should be better educated in good statistical practice and research ethics. I couldn’t agree more and would suggest that cost-effectiveness analysis is included, given that it informs policy decisions and it is generally conducted by multidisciplinary teams.

I’m now wondering what the responses would be if we did a similar survey to health economists, particularly those working in health technology assessment! Something for HESG, iHEA or ISPOR to look at for the future?

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Chris Sampson’s journal round-up for 5th February 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.

Cost-effectiveness analysis of germ-line BRCA testing in women with breast cancer and cascade testing in family members of mutation carriers. Genetics in Medicine [PubMed] Published 4th January 2018

The idea of testing women for BRCA mutations – faulty genes that can increase the probability and severity of breast and ovarian cancers – periodically makes it into the headlines. That’s not just because of Angelina Jolie. It’s also because it’s a challenging and active area of research with many uncertainties. This new cost-effectiveness analysis evaluates a programme that incorporates cascade testing; testing relatives of mutation carriers. The idea is that this could increase the effectiveness of the programme with a reduced cost-per-identification, as relatives of mutation carriers are more likely to also carry a mutation. The researchers use a cohort-based Markov-style decision analytic model. A programme with three test cohorts – i) women with unilateral breast cancer and a risk prediction score >10%, ii) first-degree relatives, and iii) second-degree relatives – was compared against no testing. A positive result in the original high-risk individual leads to testing in the first- and second-degree relatives, with the number of subsequent tests occurring in the model determined by assumptions about family size. Women who test positive can receive risk-reducing mastectomy and/or bilateral salpingo-oophorectomy (removal of the ovaries). The results are favourable to the BRCA testing programme, at $19,000 (Australian) per QALY for testing affected women only and $15,000 when the cascade testing of family members was included, with high probabilities of cost-effectiveness at $50,000 per QALY. I’m a little confused by the model. The model includes the states ‘BRCA positive’ and ‘Breast cancer’, which clearly are not mutually exclusive. And It isn’t clear how women entering the model with breast cancer go on to enjoy QALY benefits compared to the no-test group. I’m definitely not comfortable with the assumption that there is no disutility associated with risk-reducing surgery. I also can’t see where the cost of identifying the high-risk women in the first place was accounted for. But this is a model, after all. The findings appear to be robust to a variety of sensitivity analyses. Part of the value of testing lies in the information it provides about people beyond the individual patient. Clearly, if we want to evaluate the true value of testing then this needs to be taken into account.

Economic evaluation of direct-acting antivirals for hepatitis C in Norway. PharmacoEconomics Published 2nd February 2018

Direct-acting antivirals (DAAs) are those new drugs that gave NICE a headache a few years back because they were – despite being very effective and high-value – unaffordable. DAAs are essentially curative, which means that they can reduce resource use over a long time horizon. This makes cost-effectiveness analysis in this context challenging. In this new study, the authors conduct an economic evaluation of DAAs compared with the previous class of treatment, in the Norwegian context. Importantly, the researchers sought to take into account the rebates that have been agreed in Norway, which mean that the prices are effectively reduced by up to 50%. There are now lots of different DAAs available. Furthermore, hepatitis C infection corresponds to several different genotypes. This means that there is a need to identify which treatments are most (cost-)effective for which groups of patients; this isn’t simply a matter of A vs B. The authors use a previously developed model that incorporates projections of the disease up to 2030, though the authors extrapolate to a 100-year time horizon. The paper presents cost-effectiveness acceptability frontiers for each of genotypes 1, 2, and 3, clearly demonstrating which medicines are the most likely to be cost-effective at given willingness-to-pay thresholds. For all three genotypes, at least one of the DAA options is most likely to be cost-effective above a threshold of €70,000 per QALY (which is apparently recommended in Norway). The model predicts that if everyone received the most cost-effective strategy then Norway would expect to see around 180 hepatitis C patients in 2030 instead of the 300-400 seen in the last six years. The study also presents the price rebates that would be necessary to make currently sub-optimal medicines cost-effective. The model isn’t that generalisable. It’s very much Norway-specific as it reflects the country’s treatment guidelines. It also only looks at people who inject drugs – a sub-population whose importance can vary a lot from one country to the next. I expect this will be a valuable piece of work for Norway, but it strikes me as odd that “affordability” or “budget impact” aren’t even mentioned in the paper.

Cost-effectiveness of prostate cancer screening: a systematic review of decision-analytical models. BMC Cancer [PubMed] Published 18th January 2018

You may have seen prostate cancer in the headlines last week. Despite the number of people in the UK dying each year from prostate cancer now being greater than the number of people dying from breast cancer, prostate cancer screening remains controversial. This is because over-detection and over-treatment are common and harmful. Plenty of cost-effectiveness studies have been conducted in the context of detecting and treating prostate cancer. But there are various ways of modelling the problem and various specifications of screening programme that can be evaluated. So here we have a systematic review of cost-effectiveness models evaluating prostate-specific antigen (PSA) blood tests as a basis for screening. From a haul of 1010 studies, 10 made it into the review. The studies modelled lots of different scenarios, with alternative screening strategies, PSA thresholds, and treatment pathways. The results are not consistent. Many of the scenarios evaluated in the studies were more costly and less effective than current practice (which tended to be the lack of any formal screening programme). None of the UK-based cost-per-QALY estimates favoured screening. The authors summarise the methodological choices made in each study and consider the extent to which this relates to the pathways being modelled. They also specify the health state utility values used in the models. This will be a very useful reference point for anyone trying their hand at a prostate cancer screening model. Of the ten studies included in the review, four of them found at least one screening programme to be potentially cost-effective. ‘Adaptive screening’ – whereby individuals’ recall to screening was based on their risk – was considered in two studies using patient-level simulations. The authors suggest that cohort-level modelling could be sufficient where screening is not determined by individual risk level. There are also warnings against inappropriate definition of the comparator, which is likely to be opportunistic screening rather than a complete absence of screening. Generally speaking, a lack of good data seems to be part of the explanation for the inconsistency in the findings. It could be some time before we have a clearer understanding of how to implement a cost-effective screening programme for prostate cancer.

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Sofosbuvir: a fork in the road for NICE?

NICE recently completed their appraisal of the hepatitis C drug sofosbuvir. However, as has been reported in the media, NHS England will not be complying with the guidance within the normal time period.

The cost of a 24 week course of sofosbuvir is almost £70,000. Around 160,000 people are chronically infected with the hepatitis C virus in England, so that adds up to a fair chunk of the NHS budget. Yet the drug does appear to be cost-effective. ICERs differ for different patient groups, but for most scenarios the ICER is below £30,000 per QALY. In the NICE documentation, a number of reasons are listed for NHS England’s decision. But what they ultimately boil down to – it seems – is affordability.

The problem is that NICE doesn’t account for affordability in its guidance. One need only consider that the threshold has remained unchanged for over a decade to see that this is true. How to solve this problem really depends on what we believe the job of NICE should be. Should it be NICE’s job to consider what should and shouldn’t be purchased within the existing health budget? Or, rather, should it be NICE’s job simply to figure out what is ‘worth it’ to society, regardless of affordability? This isn’t the first time that an NHS organisation has appealed against a NICE decision in some way. Surely, it won’t be the last. These instances represent a failure in the system, not least on grounds of accountability for reasonableness. Here I’d like to suggest that NICE has 3 options for dealing with this problem; one easy, one hard and one harder.

The easy option

The simplest option involves the fewest changes to the NICE process. Indeed, it would involve doing pretty much what it does now, only with slightly different (and more transparent) reasoning. In this scenario NICE would explicitly ignore the problem of affordability. Its remit would cease to be the consideration of optimality on a national level and it would ignore the budget constraint. NICE’s remit would become figuring out which health technologies are ‘worth it’; i.e. would the public be willing to purchase a given technology with a given health benefit at a given cost. To some extent, therefore, NICE would become a threshold-setter. The threshold should be based on some definition of a social value of a QALY. This is the easy option for NICE as setting the threshold would be the only additional task to what they currently do. Its threshold might not change all that much, or may be a little higher.

However, even if NICE denies responsibility, clearly someone does need to take account of affordability. Given the events associated with sofosbuvir it seems that this could become the work of NHS England. NHS England could use a threshold based on the budget and current QALY-productivity in the NHS. One might expect NHS England to be in a better position to identify the local evidence necessary to determine appropriate thresholds, which would likely be much lower than NICE’s. It would also be responsible for disinvestment decisions. Given the nationwide remit of NHS England, this would still prevent postcode lotteries. The implication here, of course, is that NICE and NHS England might use different thresholds. Any number of decision rules could be used to determine the result for technologies falling between the two. Maybe this is where considerations for innovation or non-health-related equity concerns belong. It seems probable to me that NICE’s threshold would be higher than NHS England’s, in which case NICE would effectively be advising increases in the health budget. This is something that I quite like the sound of.

The hard option

Personally, I believe that NICE’s failure to justify their threshold(s) is quite a serious failing and undermines the enterprise. The hard option will involve them defining it properly, informed by current levels of QALY-productivity in the NHS. Thus properly adopting a position as a threshold-searcher, and doing the job prescribed to NHS England in the ‘easy option’. NICE guidance would therefore be informed by the current health budget and affordability, and therefore must include guidance on disinvestment. The first stage of this work has already been done. The disinvestment guidance would be the hard part. This argument has already been much discussed, and seems to be what many economists support.

I don’t find this argument entirely compelling, at least not as a solution to the affordability problem. To solve this issue NICE would need to regularly review the current threshold and revise it in light of current productivity and the prevailing health budget. It has no experience of doing this. I believe the task could be more effectively carried out by commissioning organisations (such as NHS England), who are in a better position to oversee the collection of the appropriate data and would have a public responsibility to do so. It might also be politically useful if decisions about affordability were made independently of decisions about value.

The harder option

The harder option is for there to be a paradigm shift in the way NICE – and health economics more generally – operates. It could involve programme budgeting and marginal analysis, or the Birch and Gafni approach. This might just be the best option, but it seems unlikely to happen nationally any time soon.

It’s possible that more cost-effective but unaffordable drugs are in the pipeline. Failure to address the affordability problem soon could seriously undermine NICE.

DOI: 10.6084/m9.figshare.1291123