EBMT 2018 | Cost-effectiveness of modern MM therapies

The MM Hub were delighted to attend the 44^th Annual Meeting of the European Society for Blood and Marrow Transplantation held in Lisbon, Portugal, from 18–21 March 2018. On Sunday 18 March 2018 an Intergroupe Francophone du Myélome (IFM Group) non-profit symposium was held entitled Multiple myeloma in 2018: the IFM global perspective. The session was moderated by Mohamad Mohty, from the Hospital Saint-Antoine and University Pierre & Marie Curie, Paris, France and Jean Luc Harousseau, from the University of Nantes, France. The final talk was presented by Jean Luc Harousseau, on the topic of Cost effectiveness of modern myeloma therapies.

Professor Harousseau began his talk by emphasizing the huge leaps that have been made in terms of survival with the advent of modern therapies, specifically with a doubling in mean survival in the past 10 years. In particular, young transplant-eligible patients have benefitted from a mean survival of more than 10 years with a standard of care (SOC) regimen of high-dose therapy and autologous stem cell transplant (HDT/ASCT) plus novel agents. Second-generation agents have further improved the results in relapsed and refractory multiple myeloma (RRMM), with an array of promising trials including TOURMALINE-MM1, ELOQUENT-2, ASPIRE, POLLUX, PANORAMA, and CASTOR. There are now more active agents presenting more possibilities for salvage treatment, and new agents are used sequentially. However, the cost of these new agents in MM is becoming a critical concern.

Due to increased survival rates, more patients are treated and treatments are often prescribed for long periods until disease progression. Many of the new regimens are most effective in a triplet, and even quadruplet, combination. It is estimated that in the US the cost of SOC treatment may reach $500,000 per patient or more depending on treatment duration. For example, a SOC regimen of induction, consolidation, and maintenance, followed by two salvage regimens, has been estimated to cost $1,068,361 (with a 30% rebate on that price. Therefore, a key question is whether such high drug prices have a deleterious cost to society.

One of the major consequences of such high prices is inevitably a lack of availability for all. In countries where full coverage of expensive drugs is not possible, there is no access to many of these regimens. Professor Harousseau described this situation as an “unacceptable loss of chance”. In addition, where there is limited access to private practice, there is also “unacceptable inequality”. In wealthier countries where there is full coverage of new agents, there can often be delayed access due to long negotiations with drug companies to secure the best price for all. And in countries where strict policies regarding health-care expenses exist, limitations may induce rationing. In the US, a lower compliance in uninsured or underinsured patients has been observed, leading to shorter survival rates. Lower overall survival (OS) rates have also been reported in patients with lower socioeconomic status, and bankruptcy of is not uncommon due to expensive co-payment schemes.

How can such high treatment prices be justified?

The production costs of many of these new regimens are to blame, and this is particularly the case with cellular therapies such as CAR T-cells. As with any new therapy, there is also a high risk of failure, as well as limited life duration because of possible replacement by less costly generics or biosimilars. Research and development costs of new regimens also play into the assigned price, as well as potential lack of added value compared to existing drugs.

To overcome such high prices, value-based pricing has been introduced in some countries, through formal Health Technology Assessment Agencies (HTAs). In Germany, the value is defined by the additional clinical benefit (so-called clinical added value), which is assessed by the Bundesministerium fur Gesundheit to enable fair prices for all medicinal products. The HTA agency oversees a process of continual benefit assessment and ongoing discussions at regular intervals (usually 3–6 months) following the first market launch. The philosophy is that ultimately the best treatments should be given to patients.

In the US there is no such evaluation of new drugs. Once both FDA approval and marketing authorization have been granted, there is no central negotiation and patients are then at the mercy of their individual private insurance. In Europe, EMA approval/ marketing authorization is followed by an HTA assessment of the added therapeutic value/efficiency at a national level, followed by negotiations with other countries and agencies.  

France follows a similar model to Germany, whereby the clinical added value (so-called ASMR) is assessed by the Haute Autorité de Santé (HAS), which decides whether new drugs provide additional benefit for patients compared to existing treatments. An ASMR score is then awarded depending on whether the benefit is deemed to be major (ASMR I), important (ASMR II), moderate (ASMR III), minor (ASMR IV), or leads to no clinical improvement (ASMR V). This leads to value-based pricing based on a relative effectiveness assessment (REA). A score of ASMR I–III will lead to a price comparable to those decided in other major European countries (eg. Germany, UK, Spain and Italy), an ASMR of IV can lead to a price superior to that of the comparators, and an ASMR score of V will mean that the drug will be only be reimbursed if its price is inferior to that of the comparators. 

Professor Harousseau then asked whether harmonization of drug evaluation is possible at the European level. It was explained that this can be done using a model of ‘assessment’ of available data in the form of an HTA agency report by internal assessors, ‘appraisal’ via an HTA report by an Appraisal Committee, and finally, ‘listing’ of the drug following assessment by the ministry and pricing committees. It was suggested that improvements to this process could be made by ensuring that early dialogues occur during the release of the relevant literature for a given drug and the application dossier stage, followed by joint assessments and the development of methodological guidelines for use. The pricing and reimbursement decisions could be made during the joint assessments stage, with a post-launch data collection allowing for further modifications.

What is cost-effectiveness analysis?

Cost-effectiveness (CE) analyses were introduced in the UK 20 years ago to aid with public decision-making for new regimens. The aim of such an analysis is to provide collective benefit for both those being treated and the taxpayers funding the expenditure. In 1999, the National Institute for Health and Care Excellence (NICE) was established to focus on health economics and decision making for the National Health Service (NHS). Such cost-effectiveness calculations begin with a comparative assessment of the cost-result ratio in order to define the price a country is willing, or able, to pay for a given benefit.  The result is an estimation of the direct costs and cost efficacy (euros per life years saved), cost-utility (euros per quality-adjusted life years [QALY]), and the incremental cost-effectiveness ratio (ICER). Referring to the ICER, Professor Harousseau said, “I have to insist on the fact that this is not only an economic (budget) analysis, but it is also a real medico-economic analysis of the clinical result of the cost.”

The ICER can define the threshold for the price of a drug and­ the threshold used by NICE is 20,000–30,000 £/QALY, but the threshold can be increased to 50,000 for certain cases, such as orphan diseases and those with a short life-expectancy. However, for cancer, the threshold is too low and that is where the Cancer Drugs Fund comes in to provide funding while the ICER is further assessed. In other countries the threshold is much higher, for example, Germany uses €100,000, but in France, there is no set threshold, as there is no consensus on the threshold value. So ICER is used as a tool, but not relied upon.

The decision-making process in England, described as a ‘price taking country’, is a function of a simple input of company price, calculation of QALY, comparison to the threshold, and a yes or no readout decision. In France, described as a ‘price setting country’, the process is different. The data for efficacy is reviewed first, then the efficiency of the ICER and cost/QALY, followed by price negotiations, finally leading to a decision regarding the price.

The decision-making process for carfilzomib was used as an example. In July 2017, NICE recommended the use of carfilzomib (plus dexamethasone, Kd) but only after one prior therapy that must exclude bortezomib. Based on the ENDEAVOR trial the ICER was calculated as £27,629/QALY, but based on the ASPIRE study the ICER for KRd (carfilzomib, lenalidomide, and dexamethasone) was not recommended as a cost-effective use of resources, with an estimated ICER of £41,400/QALY, with unknown OS benefit. Two separate studies also showed very different results for CE calculations for carfilzomib in the US (USD/QALY): 267,464 vs 107,520. Therefore, there are limitations to CE analysis, as the methods are complex, the reimbursement/pricing decisions are based on models, and there is a great level of uncertainty with many of the variables used. Such analyses also differ between countries.

What is the role of physicians?

Professor Harousseau concluded by explaining that physicians can assist with decision making regarding cost-effectiveness, by good clinical practice and by using only validated approaches. Cost should be considered when prescribing medicines and health economic calculations should be included in the design of clinical trials, as well as questions regarding efficiency. Finally, cost-minimizing clinical trials need to be designed, in order to see whether shorter treatments can achieve the same result at a lower price.