Estimating the Product Lifecycle Value of Trastuzumab Based on Registry Data in Sweden.

BACKGROUND AND OBJECTIVE: Trastuzumab was introduced in Sweden in 2000 for treatment of HER2-positive metastatic breast cancer (MBC) and later expanded to early breast cancer (EBC). The potential value of this innovative therapy was explored in economic evaluations; however, the extent to which these benefits were realised remains unknown. This study aims to estimate the lifecycle value of trastuzumab by combining randomised trial data with Swedish routine-care data. METHODS: Trastuzumab impact on costs and health outcomes was estimated with Markov models for MBC and EBC. Model inputs included progression/recurrence and breast cancer-related mortality data from international randomised clinical trials, and Sweden-specific non-breast cancer-related mortality, numbers treated, and costs and utilities based on data from National Registries and literature. Model predictions were validated by observed survival rates from the National Breast Cancer Registry. RESULTS: From 2000 to 2021, 3936 and 11,134 patients with HER2-positive MBC and EBC, respectively, were treated with trastuzumab, resulting in 25,844 life years and 13,436 per quality-adjusted life years (QALY) gained. Cost per QALY gained was lower in EBC (Swedish krona [SEK] 285,000/QALY) than MBC (SEK 554,000/QALY). The net-monetary value delivered (excluding drug costs) was SEK 13.714 billion, and society retained 62% of this. The modelled survival in trastuzumab-treated patients with EBC matched closely with actually observed survival in registry data. CONCLUSION: Trastuzumab provided substantial population-level health benefits for patients and society, with favourable cost effectiveness in MBC and EBC. There is some uncertainty around the magnitude of these benefits, mainly due to missing data on health outcomes and number of treated patients with MBC.

The Disease Burden and Economic Burden of Cancer in 9 Countries in the Middle East and Africa.

OBJECTIVES: The objective of this study was to characterize the epidemiological development of cancer in the Middle East and Africa since 2000 and to quantify its current economic impact. METHODS: Nine countries were studied: Algeria, Egypt, Jordan, Kuwait, Lebanon, Morocco, Saudi Arabia, South Africa, and the United Arab Emirates. Information on causes of death and disability-adjusted life-years (DALYs) was obtained from the World Health Organization. Information on cancer incidence was collected from local cancer registries and estimations by the World Health Organization. The economic burden of cancer was estimated from local health expenditure data and from age-specific mortality data. RESULTS: Between 2000 and 2019, cancer went from third-leading to second-leading cause of death (10% to 13% of all deaths) across these 9 countries. It also climbed from the sixth-leading to third-leading cause of DALYs (6% to 8% of all DALYs). New cancer cases per 100 000 inhabitants increased by 10% to 100% between 2000 and 2019, whereas future increases until 2040 range from 27% in Egypt to 208% in the United Arab Emirates, solely because of expected demographic changes. The economic burden of cancer ranged from around USD 15 per capita in the 4 African countries to USD 79 in Kuwait in 2019. CONCLUSIONS: Cancer is becoming one of the leading causes of disease burden in the Middle East and Africa. Patient numbers are expected to rise strongly in the coming decades. Increasing healthcare expenditure on appropriate cancer care is important to improve patient outcomes and can attenuate the economic impact of cancer on society.

Targeted Therapy in the Palliative Setting of Colorectal Cancer-Survival and Medical Costs.

(1) Background: Targeted therapy is used alone or together with chemotherapy in metastatic colorectal cancer. The aim of this study was to assess overall survival and medical costs in a cohort of patients with metastatic colorectal cancer. (2) Methods: Demographic and clinical characteristics of 337 patients and pathological data of colorectal tumors were retrospectively collected in this population-based study. The overall survival and medical costs for patients receiving chemotherapy plus targeted therapy were compared with those for patients receiving chemotherapy only. (3) Results: Patients administered chemotherapy plus targeted therapy were less frail and had more often RAS wild-type tumors but had higher CEA levels than patients receiving chemotherapy only. No prolonged overall survival could be observed in patients receiving palliative targeted therapy. The medical costs for patients undergoing treatment with targeted therapy were significantly higher than for patients treated only with chemotherapy; they were especially higher in the group receiving targeted therapy early than late in the palliative setting. (4) Conclusions: The use of targeted therapy in metastatic colorectal cancer leads to significantly higher medical costs when used early in the palliative setting. No positive effects of the use of targeted therapy could be observed in this study; therefore, we suggest that targeted therapy be used in later lines of palliative therapy in metastatic colorectal cancer.

Review and Assessment of Policy Options for Improving Access to Combination Therapies in Oncology in Europe.

OBJECTIVES: Combinations of on-patent therapies (CTs) are increasingly common in oncology. They cause challenges for funding and affordability, and hence patient access, especially when constituent therapies are owned by different manufacturers. The aim of our study was to develop policy proposals for the assessment, pricing, and funding of CTs and identify which might be relevant in different European countries. METHODS: Following a review of available literature, seven hypothetical policy proposals were developed and subsequently assessed through 19 semi-structured interviews with health policy, pricing, technology assessment and legal experts in seven European countries to identify those most likely to gain traction. RESULTS: Experts saw a need for agreed approaches within a country to manage affordability and funding challenges for CTs. Changes to health technology assessment (HTA) and funding models were considered unlikely, but other policy proposals were seen as mostly useful, with country-specific adaptations. Bilateral discussions between manufacturers and payers were deemed important, and less challenging and protracted than arbitrated dialogue between manufacturers. Usage-specific pricing, possibly using weighted average prices, was considered a prerequisite for the financial management of CTs. CONCLUSIONS: There is a growing need to ensure that CTs are affordable to health systems. It would appear that there is no one set of policies that is appropriate for all countries in Europe, so countries wishing to ensure that patients have (or continue to have) access to CTs of value to them must explore and implement the policies that are best suited to their general approach to funding health care and to the assessment and reimbursement of medicines.

The value of anticancer drugs - a regulatory view.

The high prices of new anticancer drugs and the marginal added benefit perceived by some stakeholders have fuelled a debate on the value of anticancer drugs in the European Union, even though an agreed definition of what constitutes a drug's value does not exist. In this Perspective, we discuss the value of drugs from different viewpoints and objectives of decision makers: for regulators, assessment of the benefit-risk balance of a drug is a cornerstone for approval; payers rely on cost-effectiveness analyses carried out by health technology assessment agencies for reimbursement decisions; for patients, treatment choices are based on personal preferences and attitudes to risk; and clinicians can use several scales (such as the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS)) that have been developed as an attempt to measure value objectively. Although a unique definition that fully captures the concept of value is unlikely to emerge, herein we discuss the importance of understanding different perspectives, and how regulators can help to inform different decision makers.

Budget projections and clinical impact of an immuno-oncology class of treatments: Experience in four EU markets.

BACKGROUND: Immunotherapies have revolutionized oncology, but their rapid expansion may potentially put healthcare budgets under strain. We developed an approach to reduce demand uncertainty and inform decision makers and payers of the potential health outcomes and budget impact of the anti-PD-1/PD-L1 class of immuno-oncology (IO) treatments. METHODS: We used partitioned survival modelling and budget impact analysis to estimate overall survival, progression-free survival, life years gained (LYG), and number of adverse events (AEs), comparing "worlds with and without" anti-PD-1/PD-L1s over five years. The cancer types initially included melanoma, first and second line non-small cell lung cancer (NSCLC), bladder, head and neck, renal cell carcinoma, and triple negative breast cancer [1]. Inputs were based on publicly available data, literature, and expert advice. RESULTS: The model [2] estimated budget and health impact of the anti-PD-1/PD-L1s and projected that between 2018-2022 the class [3] would have a manageable economic impact per year, compared to the current standard of care (SOC). The first country adaptations showed that for that period Belgium would save around 11,100 additional life years and avoid 6,100 AEs. Slovenia - 1,470 LYGs and 870 AEs avoided; Austria - respectively 4,200, 3,000; Italy - 19,800, 6,800. For Austria, the class had a projected share of about 4.5 % of the cancer care budget and 0.4 % of the total 2020 healthcare budget. For Belgium, Slovenia, and Italy - respectively 15.1 % and 1.1 %, 12.6 %, 0.6 %, and 6.5 %, 0.5 %. CONCLUSION: The Health Impact Projection (HIP) is a horizon scanning model designed to estimate the potential budget and health impact of the PD-(L)1 inhibitor class at a country level for the next five years. It provides valuable data to payers which they can use to support their reimbursement plans. POLICY SUMMARY: The model is a strategic tool which allows decisionmakers to assess the implications of policy decisions, such as additional investment, or accelerated access to IOs. It can drive tangible population health benefits by eliminating the questions around PD-(L)1 inhibitor spending and its related outcomes.

A multi-stakeholder approach in optimising patients' needs in the benefit assessment process of new metastatic breast cancer treatments.

There is a growing understanding as science evolves that different cancer types require different approaches to treatment evaluation, especially in the metastatic stages. The introduction of new metastatic breast cancer (MBC) treatments may be hindered by several elements, including the availability of relevant evidence related to disease-specific outcomes, the benefit assessment process around the evaluation of the clinical benefit and the patients' need of new treatments. The Steering Committee (SC) found that not all issues relevant to MBC patients are consistently considered in the current benefit assessment process of new treatments. Among these are overall survival, time-to-event endpoints (e.g. progression-free survival), patients' priorities, burden of disease, MBC-specific quality of life, value in delaying chemotherapy, route of administration, side effects and toxicities, treatment adherence and the benefit of real-world evidence. This paper calls on decision makers to (1) Include MBC-specific patient priorities and outcomes in the overall benefit assessments of new MBC treatments; (2) Enhance multi-stakeholder collaboration in order to improve MBC patient outcomes.

The cost of cancer in Europe 2018.

BACKGROUND: Cancer care is evolving rapidly, and costs and value of new treatments are frequently debated. Up-to-date evidence on the total cost of cancer is needed to inform policy decisions. This study estimates the cost of cancer in Europe in 2018 and extends a previous analysis for 1995-2014. METHODS: Cancer-specific health expenditure were derived from national estimates. Data on cancer drug sales were obtained from IQVIA. The productivity loss from premature mortality was estimated from data from Eurostat and the World Health Organization. Estimates of the productivity loss from morbidity and informal care costs were based on previous studies. FINDINGS: The total cost of cancer was €199 billion in Europe (EU-27 plus Iceland, Norway, Switzerland, and the United Kingdom) in 2018. Total costs ranged from €160 per capita in Romania to €578 in Switzerland (after adjustment for price differentials). Health expenditure on cancer care were €103 billion, of which €32 billion were spent on cancer drugs. Informal care costs were €26 billion. The total productivity loss was €70 billion, composed of €50 billion from premature mortality and €20 billion from morbidity. INTERPRETATION: Health expenditure on cancer care were of a similar magnitude as the sum of non-health-care costs in 2018. Over the last two decades, health spending on cancer has increased faster than the increase in cancer incidence. The productivity loss from premature mortality has decreased because of reductions in mortality in the working-age population. Trends in informal care costs and productivity loss from morbidity are uncertain because of lack of comparable data.

Achieving equal and timely access to innovative anticancer drugs in the European Union (EU): summary of a multidisciplinary CECOG-driven roundtable discussion with a focus on Eastern and South-Eastern EU countries.

The Central European Cooperative Oncology Group (CECOG) and 'ESMO Open-Cancer Horizons' roundtable discussion brought together stakeholders from several European Union (EU) countries involved in drug development, drug authorisation and reimbursement or otherwise affected by delayed and unequal access to innovative anticancer drugs. The approval process of drugs is well established and access delays can be caused directly or indirectly by national or regional decision-making processes on reimbursement. The two key aspects for those involved in reimbursement decisions are first the level of evidence required to decide and second pricing, which can be challenging for some innovative oncology compounds, especially in Eastern and South-Eastern European countries. Other important factors include: available healthcare budget; the structure and sophistication of healthcare authorities and health technology assessment processes; societal context and political will. From the point of view of the pharmaceutical industry, better alignment between stakeholders in the process and adaptive pathway initiatives is desirable. Key aspects for patients are improved access to clinical trials, preapproval availability and reports on real-world evidence. Restricted access limits oncologists' daily work in Eastern and South-Eastern EU countries. The roundtable discussion suggested considering the sequencing of regulatory approval and reimbursement decisions together with more flexible contracting as a possible way forward. The panel concluded that early and regular dialogue between all stakeholders including regulators, payers, patient stakeholders and industry is required to improve the situation.

The cost and burden of cancer in the European Union 1995-2014.

BACKGROUND: There is an intense debate about the cost of cancer and the value of new treatments. However, there is limited data on the cost of cancer in the European Union (EU) and how costs relate to the burden of disease. This paper presents new estimates on the development of the cost of cancer in the EU 1995-2014, with a focus on the major cost components: total health expenditure, cancer drugs, and production loss due to premature mortality. METHODS: Data on overall health expenditure were combined with national disease estimates to derive cancer-specific health expenditure. Data on drug sales were obtained from IMS Health, and epidemiological data were used to calculate life years lost due to cancer. FINDINGS: Health expenditure on cancer increased continuously from €35.7 billion in 1995 to €83.2 billion in 2014 in the EU and spending on cancer drugs from €7.6 billion in 2005 to €19.1 billion in 2014 (current prices). Yet the share of total health expenditure devoted to cancer was mostly constant (around 6 per cent). While expenditures on cancer drugs increased in both absolute and relative terms, other expenditures were stable or decreased, despite increases in cancer incidence driven by a growing and ageing population. Reductions in cancer mortality during working age resulted in decreasing production loss due to premature mortality. INTERPRETATION: Health spending on cancer as a share of total health expenditure is rather low and stable despite the growing incidence and relative burden of cancer. Problems to reallocate funding in health care systems under economic pressure may be one explanation and shifting costs from inpatient to ambulatory care another.

The positioning of economic principles under the changing conditions of the novel drug developmental process in cancer.

Cancer is a major burden to the health care system, presently mainly in developed countries, but is rapidly becoming a problem of similar magnitude in developing countries. Cancer ranks number two or three measured in loss of "good years of life" in Europe. The direct cost of cancer are estimated to be around 50% of total health care costs and of these costs a major part is linked to cancer drugs. With the ongoing revolution in the understanding of cancer and the development of an increasing number of new, but often very costly drugs, the health care systems in all parts of the world need to have a systematic way of evaluating new cancer drugs. Health technology assessment (HTA) now plays a major role in many parts of Europe. HTA has its focus on determining the value of new innovations in order to balance allocation of health care resources in a fair and equal way. This paper reviews the HTA process in general and for cancer drugs specifically. The key findings are that cancer drugs must be evaluated in a similar way as other health care technologies. One must however take into account that cancer drugs are often approved with a high level of uncertainty. Thus, it is of key importance that not only clinical efficacy, i.e., effect in pivotal clinical trials, is taken into account, but that there is a great need for follow-up studies so that post regulatory approval is able to properly measure population based effects [clinical effectiveness (CLE)].

Clinical experience with Zarzio® in Europe: what have we learned?

Biosimilars are similar, but non-identical, versions of existing biological drugs for which patents have expired. Despite the rigorous approval process for biosimilars, concerns have been expressed about the efficacy and safety of these products in clinical practice. Biosimilars of filgrastim, based on the originator product Neupogen®, have been available since 2008 and are now in widespread clinical use in Europe and elsewhere. Three biosimilar G-CSFs have been approved based on a combination of physicochemical and biological protein characterisation, pharmacokinetic and pharmacodynamic assessment in healthy volunteers and efficacy and safety data in patients with cancer. To assess whether biosimilars are effective in the real-world clinical practice setting, a pooled analysis of five post-approval studies of biosimilar G-CSF (Zarzio®) that included 1,302 adult patients who received at least one cycle of chemotherapy with G-CSF support for the prevention of neutropenia was conducted. A total of 36 % of patients had a febrile neutropenia risk of >20 %, while 39.6 % had a risk of 10-20 % based on chemotherapy regimen. The occurrence of severe or febrile neutropenia was within the range of that observed in previous studies of originator G-CSF. In addition, the safety profile of Zarzio® was consistent with that reported for originator G-CSF and the known safety profile of G-CSF. Initial concerns about the use of biosimilars, at least with regard to biosimilar G-CSFs, appear to be unfounded. Adoption of cost-effective biosimilars should help reduce healthcare costs and improve patient access to biological treatments.

Cancer vaccines and immunotherapeutics: challenges for pricing, reimbursement and market access.

Public payment is key to market access for new therapeutics including cancer vaccines and cancer immunotherapeutics. However, the methodology for economic evaluation aimed at informing decisions about pricing and reimbursement is different for cancer vaccines, such as HPV for preventing the occurrence or incidence of cancer, and immunotherapeutics for treatment of patients with manifest cancer. Vaccination against HPV is a traditional public health intervention, where the role of economic evaluation is to inform decisions about optimal vaccination strategies. The decision is about funding for a vaccination program, aimed at vaccinating a defined population at risk, either at a national or regional level. The methodology of economic evaluation is based on statistical modeling of number of cases prevented over a long time period, and the costs and health outcome related to this, for different vaccination strategies For immunotherapeutics, the role of economic evaluation is to assist decisions about reimbursement and guidelines for treatment of patients with establish disease, very often at advanced stages with short life expectancy. The focus is on alternative treatment options, and the costs and outcomes associated with these. Alternatives may be best supportive care, immunotherapeutics or other treatments like surgery, radiotherapy and other anti-cancer drugs. From an economic perspective the type of therapy does not matter, only costs and outcome associated with the relevant alternatives. The main controversy about reimbursement of immunotherapeutics, as with other new cancer drugs, has been the cost of treatment, mainly determined by the price of the therapy, in relation to the expected benefits in terms of survival and quality of life. This paper reviews the evidence on cost-effectiveness, the reimbursement decisions made, and the impact on market access for new immunotherapeutics. Sipuleucel-T (Provenge(®)) and abiraterone (Zytiga(®)) for treatment of prostate cancer and ipilimumab (Yervoy(®)) as well as vemurafenib (Zelboraf(®)) for treatment of metastatic melanoma are used as examples of the economic issues involved in analysis and decision-making.

Trastuzumab use in breast cancer patients in the six Health Care Regions in Sweden.

BACKGROUND: Approximately 14% of Early Breast Cancers, EBCs, and 25% of Metastatic BCs, MBCs, are HER2 positive. There is an effective treatment (trastuzumab) for both EBC (9% increased absolute disease free survival at five years) and MBC (five to nine months' prolonged overall survival). Patients with BC are treated within each of the six different Health Care Regions (HCRs) in Sweden. This aim of this project was to study the introduction and usage of trastuzumab in BC in the six HCRs in Sweden. MATERIALS AND METHODS: We used official sales data and cancer statistics in the model, and HER2 positive proportions of 25% (prevalent population in year 2000; first year of trastuzumab sales) and 14% and treatment times of 38 weeks and 52 weeks for MBC and EBC, respectively, based on clinical trial data. We used years 2000-2004 for the MBC analyses. In year 2005 data on trastuzumab in EBC were presented, and approval came in year 2006. We studied years 2006-2008 for the use in both EBC and MBC. RESULTS: The percentage trastuzumab treated MBC patients for the entire period in the different HCRs (quarter 4 2000 to end 2004) was: North 57%, Stockholm 48%, South East 40%, South 17%, Uppsala 52%, West 34%. The Sweden average was 40%. The percentage treated patients (MBC and EBC), years 2006-2008 in the different HCRs was: North 68%, Stockholm 75%, South East 43%, South 44%, Uppsala 74%, West 43%. The Sweden average was 59%. CONCLUSION: The differences in usage of trastuzumab may be explained by variable interpretations of the clinical data and applications in clinical practice, budget issues and differences in coordination, experience and training.

Forecasting drug utilization and expenditure in a metropolitan health region.

BACKGROUND: New pharmacological therapies are challenging the healthcare systems, and there is an increasing need to assess their therapeutic value in relation to existing alternatives as well as their potential budget impact. Consequently, new models to introduce drugs in healthcare are urgently needed. In the metropolitan health region of Stockholm, Sweden, a model has been developed including early warning (horizon scanning), forecasting of drug utilization and expenditure, critical drug evaluation as well as structured programs for the introduction and follow-up of new drugs. The aim of this paper is to present the forecasting model and the predicted growth in all therapeutic areas in 2010 and 2011. METHODS: Linear regression analysis was applied to aggregate sales data on hospital sales and dispensed drugs in ambulatory care, including both reimbursed expenditure and patient co-payment. The linear regression was applied on each pharmacological group based on four observations 2006-2009, and the crude predictions estimated for the coming two years 2010-2011. The crude predictions were then adjusted for factors likely to increase or decrease future utilization and expenditure, such as patent expiries, new drugs to be launched or new guidelines from national bodies or the regional Drug and Therapeutics Committee. The assessment included a close collaboration with clinical, clinical pharmacological and pharmaceutical experts from the regional Drug and Therapeutics Committee. RESULTS: The annual increase in total expenditure for prescription and hospital drugs was predicted to be 2.0% in 2010 and 4.0% in 2011. Expenditures will increase in most therapeutic areas, but most predominantly for antineoplastic and immune modulating agents as well as drugs for the nervous system, infectious diseases, and blood and blood-forming organs. CONCLUSIONS: The utilisation and expenditure of drugs is difficult to forecast due to uncertainties about the rate of adoption of new medicines and various ongoing healthcare reforms and activities to improve the quality and efficiency of prescribing. Nevertheless, we believe our model will be valuable as an early warning system to start developing guidance for new drugs including systems to monitor their effectiveness, safety and cost-effectiveness in clinical practice.

Cost-effectiveness of HER2 testing and trastuzumab therapy for metastatic breast cancer.

BACKGROUND: Trastuzumab is a monoclonal antibody that together with chemotherapy significantly improves time to progression and overall survival for metastatic breast cancer patients with tumours overexpressing HER2. The aim of this study was to analyse the cost-effectiveness of HER2 testing and trastuzumab in combination with chemotherapy compared with chemotherapy alone from a societal perspective in a Swedish setting. MATERIAL AND METHODS: We used a Markov state transition model to simulate HER2 testing and subsequent treatment in a hypothetical cohort of 65 year old metastatic breast cancer patients. Outcomes included life-time costs, quality adjusted life years (QALY), and cost per QALY gained. Five different testing and treatment strategies were evaluated. RESULTS: We estimated the cost per QALY gained to be about 485,000 SEK for the strategy of IHC testing for all patients, with FISH confirmation of 2+ and 3+, and trastuzumab and chemotherapy treatment for FISH positive patients. For the strategy of FISH testing for all patients, with trastuzumab and chemotherapy for FISH positive patients, we estimated the cost per QALY gained to about 561,000 SEK. The remaining testing and treatment strategies were dominated. Results were sensitive to changes in utilities, the risk of breast cancer related death, and test characteristics. CONCLUSION: Our analysis indicate that FISH testing for all patients with trastuzumab and chemotherapy treatment for FISH positive patients is a cost-effective treatment option from a societal perspective.