## Abstract

Background

The management of cancer is predicated on the availability and affordability of anticancer therapies, which may be either curative or noncurative.

Aim

The primary aims of the study were to evaluate (i) the formulary availability of licensed antineoplastic medicines across Europe; (ii) patient out-of-pocket costs for the medications and (iii) the actual availability of the medication for a patient with a valid prescription.

Materials and methods

The survey tool was based on the previous ESMO studies that addressed the availability and accessibility of opioids for the management of cancer pain. A total of 185 field reporters from 49 countries were invited to participate. The preliminary set of data was posted on the ESMO website for open peer-review, and amendments have been incorporated into the final report.

Results

There are substantial differences in the formulary availability, out-of-pocket costs and actual availability for many anticancer medicines. The most profound lack of availability is in countries with lower levels of economic development, particularly in Eastern Europe, and these are largely related to the cost of targeted agents approved in the last 10 years. Discrepancies are less profound among medications on the WHO model essential medicines list (EML) for cancer and in curative settings. However, medicine shortages also affect WHO EML medicines, with relevant therapeutic implications for many patients.

Conclusions

The cost and affordability of anticancer treatments with recent market approval is the major factor contributing to inequity of access to anticancer medications. This is especially true with regards to new medications used in the management of EGFR- or ALK-mutated non-small-cell lung cancer, metastatic melanoma, metastatic renal cell cancer, RAS/RAF wild-type metastatic colorectal cancer, HER2 overexpressed breast cancer and castration-resistant metastatic prostate cancer.

## introduction

Contemporary management of cancer is predicated on the availability and affordability, particularly personal affordability in many countries, of anticancer therapies. These therapies may be either curative or noncurative, and in the latter case, the aim of treatment is to either prolong survival and/or improve the quality of life. The repertoire of anticancer medicines has expanded substantially and rapidly in recent years. While this has considerably improved long-term survival rates for some cancers, more often it is duration and quality of survival that have improved. However, improvements in outcomes have come at a very substantial cost, and in the past decade, the average price of new anticancer agents has more than doubled, from $4500 to >$10 000 per month [1, 2].

The accessibility of any medication is dependent upon a complex sequence of processes: licensing; manufacture and/or importation; procurement by government insurers or hospitals; budget allocations for purchase by the public sector; the application of evidence-based clinical practice guidelines and the degree to which a medication is subsidized or reimbursed (which impacts upon a patient's out-of-pocket costs) [3]. This latter consideration is critical since out-of-pocket expenses to patients contribute to financial distress [4, 5] or toxicity [6] associated with treatment procurement and/or lack of realistic access. Out-of-pocket costs are also due to price ‘mark-ups’ by wholesalers, hospitals and sometimes even doctors and pharmacists [7, 8]. Furthermore, access to medication may be confounded by requirements for preapproval for the provision of subsidized medications, and this may, in some instances, cause substantial delay in the initiation of treatment [9].

Europe is politically and economically heterogeneous. All of the Western European economies and Israel are categorized by the World Bank as high-income countries. In contrast, with the exception of Hungary and the Czech Republic, all of the Eastern European economies are considered upper-middle income [10]. Previous studies have highlighted that the cost of care delivery [11], cost of anticancer medications [8], total expenditure on cancer medicines and cancer outcomes [12–14] vary substantially across Europe and that these are influenced by a country's level of economic and social development [14, 15].

The European Union (EU) has repeatedly expressed a commitment to improving the equity of healthcare services across Europe [16, 17]. This approach has been endorsed by the European Society for Medical Oncology (ESMO), which aims for high-level cancer care to be available in all European countries. An essential step in addressing inequalities in the provision of medical oncology services is to collate a comprehensive baseline dataset that includes the formulary availability and actual availability of anticancer medications, as well as out-of-pocket costs to patients.

There is general and evidence-based support for three common issues regarding the availability of anticancer medicines for the treatment of cancer in Europe: (i) formulary limitations: while these have been generally described, there has been no comprehensive mapping of anticancer medicine formularies in Europe; (ii) actual availability: there are well-documented instances of shortages that have impaired care delivery in multiple sites in Europe [18, 19] and (iii) barriers to access to new anticancer medications, either because of resource allocation issues or prohibitive out-of-pocket expense to patients.

The primary aims of the study were to evaluate (i) the formulary availability of licensed antineoplastic medicines across Europe; (ii) patient out-of-pocket costs for the medications and (iii) the actual availability of the medication for a patient with a valid prescription. Secondary aims were to obtain information relating to the factors adversely impacting the availability of antineoplastic agents and reimbursement preapproval requirements and delays. This report focuses on the primary aims of the study.

## methodology

### project development

The study was developed by ESMO with input and cooperation from the ESMO Executive Board, ESMO National Representatives, ESMO EU Policy Committee ESMO Education Committee, ESMO Practising Oncologists Committee, the ESMO Global Policy Committee (formerly the Emerging Countries Committee) as well as the ESMO Faculty and three collaborating partners: the Union for International Cancer Control (UICC), the Institute of Cancer Policy of King's College London and the European Society of Oncology Pharmacy (ESOP). Implementation and data analysis were carried out by independent researchers from the collaborating partner organizations. The World Health Organization (WHO) was a supporting partner in this project which is part of an ongoing 3-year work plan between ESMO and the WHO.

#### study format and data collection

The survey tool was based on the previous ESMO collaborative studies that addressed the availability and accessibility of opioids for the management of cancer pain [20, 21]. Additional sections were added to address issues specific to anticancer agents and were reviewed by the collaborating partner organizations.

The survey consisted of two parts: part one consisted of six general questions regarding the country's healthcare system; and part two surveyed the formulary of anticancer medications used to treat 14 common disease situations (Table 1). The list of anticancer medications for each disease entity was derived from ESMO and National Comprehensive Cancer Network (NCCN) guidelines and ‘UpToDate’ subject reviews and included medications approved by either the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) as of March 2014. Field reporters were asked to indicate the following for each medication: whether it was permissible to prescribe the cancer medicine for this indication; if the medication is reimbursed for this indication; the proportion of the full retail price the average patient pays for the medication; preauthorization requirements and delays of >4 weeks in the approval process; the actual availability of the medication for most patients in the country under question and, in cases where the medication is not always available, the reason(s) for lack of availability.

Table 1.

Diseases surveyed

 Breast cancer adjuvantBreast cancer metastaticLung cancerColorectal cancerProstate cancerOvarian cancerSarcomaPancreatic cancerGerm cell cancerRenal cell cancerGastrointestinal germ cell tumors GISTUrothelial cancersGastric and esophageal cancerMelanoma
 Breast cancer adjuvantBreast cancer metastaticLung cancerColorectal cancerProstate cancerOvarian cancerSarcomaPancreatic cancerGerm cell cancerRenal cell cancerGastrointestinal germ cell tumors GISTUrothelial cancersGastric and esophageal cancerMelanoma

ESMO and the collaborating partners sought to identify a minimum of two field reporters through an iterative process for each country. The field reporters were derived from either national or approved representatives of the professional organizations collaborating in this project; they could be either oncologists or oncology pharmacists. A total of 185 field reporters from 49 countries were invited to participate.

Electronic survey forms were developed on a Qualtrics platform, which facilitated automatic data entry into an Excel spread sheet for analysis. Data submitted between 4 April 2014 and 17 June 2014 by the two field reporters from each country were crosschecked by the principle investigator (Nathan Cherny). When discrepancies between reporters were identified, clarifications were requested. When discrepancies persisted, priority was given to the response provided by the most highly credentialed reporter and where supportive data were presented. The principle investigator tabulated and graphically presented the data in the format used in the previous ESMO surveys addressing opioid availability for the management of cancer pain [20].

The results pertaining to the first two aims of the study are presented in figures labeled ‘Formulary availability and out of pocket cost’. These color-coded figures indicate (in black) medications that are not on formulary (aim 1), and for drugs on formulary, the percentage of the full price that patients pay out-of-pocket (after state or insurance reimbursement) (aim 2). The results pertaining to aim 3 are presented in figures labeled ‘Actual availability’. These color-coded figures indicate (in black) medications that are not on formulary, and for drugs on formulary, the percentage of instances in which a patient with a valid prescription can actually access the prescribed medication.

A preliminary report of the findings was presented at the ESMO Madrid Congress in September 2014. The preliminary data were posted on the ESMO website for external validation between November 2014 and February 2015. Invitations were sent to all members of the coordinating and collaborating partner organizations to review the data and to submit any corrections or amendments. Amendments were collated, crosschecked and incorporated into the final report that was completed in May 2015.

For presentation purposes, data are presented for 27 ‘Eastern European’ countries and 21 ‘Western European’ countries including Cyprus, Israel and Turkey, broadly based on the economic demarcation between ‘old’ and ‘new’ Europe. For clarity of presentation, and to highlight findings of inequity and impact, disease entities were pragmatically classified as ‘broad disparity’, ‘segmental disparity’, ‘patchy disparity’ or ‘low disparity’ based upon the degree of disparity in formulary availability, out-of-pocket cost and accessibility of anticancer medicines used for each disease entity between Eastern and Western European country clusters and to emphasize those disease entities that are most strongly affected by disparities.

## results

Reports were submitted by 126 individual reporters from 48 countries (Table 2). The respondents included 31 oncology pharmacists (from 22 countries) and 95 oncologists. Additional peer-review data were submitted by a further 57 reporters from 17 countries.

Table 2.

Number of reporters for each country

Number of field reporters Western European countries Eastern European countries
Holland, Spain (N = 2)
Austria, Holland, Belgium, Germany, Switzerland (N = 5)
Cyprus, Italy (N = 2) Bulgaria, Croatia, Estonia, Hungary, Romania, Slovenia (N = 6)
Israel, Norway, Turkey (N = 3) Belarus, Kyrgyzstan, Poland (N = 3)
France, Greece, Iceland, Ireland, Sweden, UK (N = 6) Albania, Bosnia and Herzegovina, Czech Republic, Malta, Russian Federation, Serbia (N = 6)
Denmark, Finland, Luxemburg (N = 3) Armenia, Georgia, Kazakhstan, Kosovo, Latvia, Lithuania, Macedonia; Montenegro, Slovakia, Turkmenistan, Ukraine (N = 12)
Number of field reporters Western European countries Eastern European countries
Holland, Spain (N = 2)
Austria, Holland, Belgium, Germany, Switzerland (N = 5)
Cyprus, Italy (N = 2) Bulgaria, Croatia, Estonia, Hungary, Romania, Slovenia (N = 6)
Israel, Norway, Turkey (N = 3) Belarus, Kyrgyzstan, Poland (N = 3)
France, Greece, Iceland, Ireland, Sweden, UK (N = 6) Albania, Bosnia and Herzegovina, Czech Republic, Malta, Russian Federation, Serbia (N = 6)
Denmark, Finland, Luxemburg (N = 3) Armenia, Georgia, Kazakhstan, Kosovo, Latvia, Lithuania, Macedonia; Montenegro, Slovakia, Turkmenistan, Ukraine (N = 12)

### diseases with high levels of disparity in out-of-pocket cost and availability

High disparity refers to disease entities in which major disparities in formulary availability, out-of-pocket cost and accessibility are observed for most agents used in the contemporary treatment of a disease. This was observed in melanoma and renal cell cancer.

#### melanoma

In contrast to the notable exceptions of interferon and dacarbazine, which are older, less expensive and less effective therapies, profound differences were observed between Western and Eastern Europe in the availability and/or out-of-pocket cost to patients of all the recent biological treatments for the management of metastatic melanoma. In contrast to Western Europe, where there was widespread availability of either free or highly subsidized access to expensive and new biological and molecularly targeted agents, with a few notable exceptions (Czech Republic, Montenegro and Slovenia), many of these medications were either unavailable or only available at full cost to patients in Eastern Europe (Figure 1). The medications were almost always available in Western Europe when prescribed, but much less so in Eastern Europe (Figure 2). Only a minority of countries in both regions request preapproval for reimbursement for these agents.

Figure 1.

Melanoma medications: formulary availability and out-of-pocket costs.

Figure 1.

Melanoma medications: formulary availability and out-of-pocket costs.

Figure 2.

Melanoma medications: actual availability.

Figure 2.

Melanoma medications: actual availability.

#### renal cell cancer (Figures 3 and 4)

Profound differences were observed between Western and Eastern Europe in the availability and/or out-of-pocket cost of all the recent biological treatments for the management of metastatic renal cell cancer. In contrast to Western Europe, where there was widespread availability of either free or highly subsidized access to expensive and new biological and molecularly targeted agents, with a few notable exceptions (Belarus, Czech Republic, Hungary, Montenegro, Slovenia and Ukraine), many of these medications were either unavailable or only available at full cost to patients in Eastern Europe (Figure 3). The medications were almost always available in Western Europe when prescribed, less so in Eastern Europe (Figure 4). Preapproval for reimbursement for these agents was commonplace in both regions, but this process resulted in treatment delays of >4 weeks only in a few countries.

Figure 3.

Renal cell cancer: formulary availability and out-of-pocket costs.

Figure 3.

Renal cell cancer: formulary availability and out-of-pocket costs.

Figure 4.

Renal cell cancer: actual availability.

Figure 4.

Renal cell cancer: actual availability.

### disease entities with segmental disparities in out-of-pocket cost and availability

Segmental disparity refers to disease entities in which major disparities in formulary availability, out-of-pocket cost and accessibility are limited to distinct subgroups of patients defined by their biological or disease status.

#### lung cancer

The disease-modifying therapies used in the management of lung cancer can broadly be divided into chemotherapy formulations and new molecularly targeted agents used either in the management of EGFR- or ALK-mutated non-small-cell lung cancer or for the reduction of morbidity from bone metastases. Overall, most of the relevant chemotherapy options were available and subsidized in Eastern and Western Europe. Substantial discrepancies were seen among the chemotherapy agents in a range of Eastern European countries, particularly regarding the therapeutic options of etoposide tablets, pemetrexed, topotecan and oral vinorelbine tablets. This discrepancy mainly concerns a cluster of countries including Armenia, Georgia, Kosovo, Kyrgyzstan, Latvia, Lithuania and the Russian Federation. Major discrepancies were observed in the availability of targeted therapy for patients suffering from non-small-cell lung cancer subtypes with either EGFR or ALK mutations [22] (Figures 5 and 6). In contrast to Western Europe, where these medications are widely available and generally fully subsidized, in many Eastern European countries they were either unavailable or available only at full cost to patients. Requirement for reimbursement preapproval is commonplace in those countries in which new molecularly targeted therapies are available and reimbursed. In Western Europe, this requirement rarely leads to treatment delays of >4 weeks. Substantial delays were more common in those Eastern European countries where these medications were available and subsidized. (Complete tables are available in supplementary file, available at Annals of Oncology online.)

Figure 5.

EGFR-mutated non-small-cell lung cancer: formulary availability and out-of-pocket costs.

Figure 5.

EGFR-mutated non-small-cell lung cancer: formulary availability and out-of-pocket costs.

Figure 6.

EGFR-mutated non-small-cell lung cancer: actual availability.

Figure 6.

EGFR-mutated non-small-cell lung cancer: actual availability.

#### colorectal cancer

The core chemotherapy medications for the management of colorectal cancer are 5-FU, capecitabine, irinotecan and oxaliplatin, which are widely available and generally subsidized in Eastern and Western Europe. Bevacizumab, which has modest incremental benefit [22], is widely available in Eastern and Western Europe. However, in Eastern Europe, it is available only at full cost to patients in Armenia, Georgia, Latvia, Macedonia and Malta. Three expensive agents of limited benefit (regorafenib, raltitrexed and aflibercept) [22] are less available than other agents in Western Europe and almost never available other than at full cost in Eastern Europe. The most dramatic discrepancies are observed for the two agents that have been shown to substantially improve overall survival of patients with K-RAS, N-RAS and B-RAF wild-type metastatic colorectal cancer: cetuximab and panitumumab [22] (Figures 7 and 8). These are almost universally available and fully subsidized in Western Europe, while in Eastern Europe they were rarely subsidized other than in Bulgaria, the Czech Republic, Montenegro, Poland, Slovenia, Slovakia and the Ukraine. Many countries require reimbursement preapproval for expensive agents, although delays of >4 weeks caused by this process were very infrequent. (Complete tables are available in supplementary file, available at Annals of Oncology online.)

Figure 7.

RAS/RAF wild-type metastatic colorectal cancer: formulary availability and out-of-pocket costs.

Figure 7.

RAS/RAF wild-type metastatic colorectal cancer: formulary availability and out-of-pocket costs.

Figure 8.

RAS/RAF wild-type metastatic colorectal cancer: actual availability.

Figure 8.

RAS/RAF wild-type metastatic colorectal cancer: actual availability.

#### metastatic breast cancer

The longitudinal management of patients with metastatic breast cancer is complex and is influenced by the underlying disease biology, in particular as to whether tumors are sensitive to hormonal manipulations or if they overexpress HER2. A broad range of therapeutic options are generally available and highly subsidized for patients with hormone-sensitive breast cancer in both Western and Eastern Europe. Fulvestrant, usually used as a third-line hormonal intervention, is either unavailable or available only at full cost in most Eastern European countries (Figures 9 and 10). Most of the older chemotherapy agents are available at no or minimal cost in all Western European countries, except Malta, and most Eastern European countries, except Armenia, Kyrgyzstan and Montenegro where the patients need to pay full price for many of these agents. Albumin-bound paclitaxel, eribulin, everolimus, liposomal doxorubicin and ixabepilone, all of which are expensive agents with modest clinical benefit [22], are generally available at no or low cost in Western Europe and are either unavailable or available only at full cost to patients in most Eastern European countries. Trastuzumab, used in the management of HER2 overexpressed breast cancer, is widely available at no cost in all Western European and most Eastern European countries (except Armenia, Georgia, Kosovo and Uzbekistan). However, with few exceptions, other HER2 targeted agents, including pertuzumab, TDM-1 and lapatinib, are only available at full cost in most Eastern European countries, as well as in Cyprus, Malta and Turkey (Figures 9 and 10). Preapproval is commonly required in many countries when reimbursement was available for expensive agents. This process infrequently causes treatment delays of >4 weeks. (Complete tables are available in supplementary file, available at Annals of Oncology online.)

Figure 9.

Metastatic breast cancer medications for third-line hormonal and HER2 amplified: cancers: formulary availability and out-of-pocket costs.

Figure 9.

Metastatic breast cancer medications for third-line hormonal and HER2 amplified: cancers: formulary availability and out-of-pocket costs.

Figure 10.

Metastatic breast cancer medications for third-line hormonal and HER2 amplified: cancers: actual availability.

Figure 10.

Metastatic breast cancer medications for third-line hormonal and HER2 amplified: cancers: actual availability.

#### prostate cancer

Whereas first-line therapy with LHRH agonists and testosterone antagonists are widely available at minimal out-of-pocket expense to patients, most Eastern European countries do not subsidize cabazitaxel, abiraterone, enzalutamide or radium 223, and availability of these agents is often limited (Figures 11 and 12). (Complete tables are available in supplementary file, available at Annals of Oncology online.)

Figure 11.

Castrate-resistant prostate cancer: formulary availability and out-of-pocket costs.

Figure 11.

Castrate-resistant prostate cancer: formulary availability and out-of-pocket costs.

Figure 12.

Castrate-resistant prostate cancer: actual availability.

Figure 12.

Castrate-resistant prostate cancer: actual availability.

### diseases with patchy disparities in out-of-pocket cost and availability

Patchy disparity refers to disease entities in which disparities in formulary availability, out-of-pocket cost and accessibility are limited or less severe.

#### gastric and esophageal cancer

Out-of-pocket expense was greater, and availability was slightly less for capecitabine and oxaliplatinum in some Eastern European countries, in particular Armenia, Kyrgyzstan, Lithuania and Uzbekistan, compared with Western European countries. For those patients with tumors overexpressing HER2, trastuzumab was widely available without out-of-pocket cost in Western Europe but in Eastern Europe it was either unavailable or only available at full cost in 11/27 of the countries surveyed (Albania, Armenia, Belarus, Croatia, Kyrgyzstan, Latvia, Romania, the Russian Federation, Serbia and Uzbekistan). (Complete tables are available in supplementary file, available at Annals of Oncology online.)

#### ovarian cancer

Minor discrepancies between Western and Eastern Europe were observed regarding the availability and out-of-pocket cost for patients for topotecan and etoposide tablets. Major discrepancies were observed regarding the out-of-pocket cost and availability of liposomal doxorubicin and bevacizumab for the management of patients with high-risk ovarian cancer. (Complete tables are available in supplementary file, available at Annals of Oncology online.)

#### sarcoma

Major discrepancies between Eastern and Western Europe were observed regarding the out-of-pocket cost for patients and availability of the three more expensive agents (pazopanib, trabectedin and liposomal doxorubicin) used for this indication. (Complete tables are available in supplementary file, available at Annals of Oncology online.)

#### gastrointestinal stromal tumors

Imatinib is widely available in Eastern and Western Europe for the management of gastrointestinal stromal tumors (GIST). Imatinib is generally available at no out-of-pocket cost to patients, even in Eastern Europe. Alternative tyrosine kinase inhibitors, including sunitinib, sorafenib and regorafenib, have variable out-of-pocket cost and availability in both Western and Eastern Europe. However, in general, these medicines were associated with greater out-of-pocket expense and lower availability in Eastern Europe. (Complete tables are available in supplementary file, available at Annals of Oncology online.)

#### pancreatic cancer

Whereas gemcitabine and cisplatinum are widely available at minimal out-of-pocket expense in all countries, many Eastern European countries do not subsidize irinotecan, oxaliplatin or capecitabine. The most extreme disparities were observed regarding albumin-bound paclitaxel which is subsidized and available in most Western European countries (14/21), but only in 5/27 Eastern European countries. (Complete tables are available in supplementary file, available at Annals of Oncology online.)

### diseases with lower levels of disparity in out-of-pocket cost and availability

Low disparity refers to disease entities in which major disparities in formulary availability, out-of-pocket cost and accessibility are not observed.

#### breast cancer in the adjuvant setting

With very few exceptions, most of the agents used in adjuvant management of early-stage breast cancer were highly subsidized and widely available in both Eastern and Western Europe. Importantly, this was also true for trastuzumab, which is the most expensive agent used in the adjuvant management of breast cancer. Trastuzumab was not subsidized in four Eastern European countries (Armenia, Georgia, Kyrgyzstan and Uzbekistan) and is only available at full cost to patients in these countries. There is no consensus regarding the merit of zoledronate in the adjuvant setting, and this is reflected in greater variability in out-of-pocket cost and availability for this single agent. Reimbursement preapproval was commonly requested for trastuzumab and other expensive agents, but this process rarely caused delays in therapy of >4 weeks. (Complete tables are available in supplementary file, available at Annals of Oncology online.)

#### germ cell tumors

Germ cell tumors are highly curable using a range of relatively inexpensive cytotoxic agents. What little variability in cost and availability was observed was related to medications used in the setting of highly refractory disease, such as taxanes and gemcitabine. Reimbursement preapproval for agents used in this setting was rarely required. (Complete tables are available in supplementary file, available at Annals of Oncology online.)

#### urothelial cancers

The chemotherapeutic agents used in the management of early-stage metastatic urothelial cancer are relatively inexpensive. With the exception of Kyrgyzstan, these agents are widely available and highly subsidized. (Complete tables are available in supplementary file, available at Annals of Oncology online.)

### correlations with world health organization model list of essential medicines

The WHO Model List of Essential Medicines, including cancer medicines, has recently been updated in April 2015 [23]. This update included the addition of 16 new medicines, including capecitabine (for colorectal and breast cancer), oxaliplatin (for adjuvant and metastatic colorectal cancer), irinotecan (for metastatic colorectal cancer), vinorelbine (for non-small-cell lung cancer and metastatic breast cancer), anastrozole (for adjuvant and metastatic breast cancer) and two very high-cost medications: imatinib (for GIST tumors) and trastuzumab (for adjuvant and metastatic HER2 overexpressed breast cancer). With relatively few exceptions (most notably in Kyrgyzstan, Armenia and Belarus), most of these medications are available with no out-of-pocket cost to patients and are reported as being always or usually available (Figures 13 and 14). However, problems impeding actual availability were reported more commonly in a cluster of Eastern European countries, including Albania, Armenia, Belarus, Georgia, Hungary, Kosovo, Kyrgyzstan, Latvia, Slovenia, Slovakia and Ukraine.

Figure 13.

(A) Anticancer medications on World Health Organization Essential Medicines List 2015: formulary availability and out-of-pocket costs. (B) Anticancer medications on World Health Organization Essential Medicines List 2015: formulary availability and out-of-pocket costs.

Figure 13.

(A) Anticancer medications on World Health Organization Essential Medicines List 2015: formulary availability and out-of-pocket costs. (B) Anticancer medications on World Health Organization Essential Medicines List 2015: formulary availability and out-of-pocket costs.

Figure 14.

(A) Anticancer medications on World Health Organization Essential Medicines List 2015: actual availability. (B) Anticancer medications on World Health Organization Essential Medicines List 2015: actual availability.

Figure 14.

(A) Anticancer medications on World Health Organization Essential Medicines List 2015: actual availability. (B) Anticancer medications on World Health Organization Essential Medicines List 2015: actual availability.

## discussion

There are large and clinically significant differences in the formulary availability, out-of-pocket costs and actual availability for many anticancer medicines in Europe. These differences are most pronounced in countries with lower levels of economic development and low GDP per capita, particularly in Eastern Europe. The potential impact of these disparities is greatest in the care of patients with incurable diseases where improved gains in patient outcomes are dependent on the availability of expensive anticancer agents. Such diseases include EGFR- and ALK-mutated non-small-cell lung cancer, metastatic melanoma, metastatic renal cell cancer, RAS/RAF wild-type colorectal cancer, Her-2-mutated metastatic breast cancer and castration-resistant metastatic prostate cancer. Cross-correlation of this data with magnitude of clinical benefit data derived from the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) indicates that many of these medications are associated with significant clinical benefit [22].

The discrepancies in formulary availability and out-of-pocket costs are less pronounced between the Western European countries and among anticancer medicines on the WHO Model List of Essential Medicines and among those used primarily in curative settings. This latter point is best illustrated by the study's findings in relation to trastuzumab in the setting of adjuvant breast cancer for HER2-positive disease and imatinib for GIST which, though expensive, are subsidized and available in most countries. The discrepancies are least when curative treatments only require classical anticancer medicines and not new molecularly targeted agents, such as in the management of germ-cell tumors, urothelial cancer and gastroesophageal cancer. However, there are also serious gaps in availability of basic chemotherapeutic medicines in many Central and Eastern European countries.

### disclaimers

The information presented in this survey is a time-constrained ‘snapshot’ of the situation, as was reported during the survey period, and it will be subject to change over time. Consequently, this dataset does not incorporate newer immunotherapies that were introduced to the therapeutic repertoire since the study was designed and administered.

The data were derived from practicing clinicians and oncology pharmacists working in the field and not from state authorities or statutory bodies. Reporting physicians were asked to consult with regulatory authorities in circumstances, in which they were unsure of cost or formulary issue. The accuracy of the data is dependent on the reporting accuracy of field reporters and their due diligence in verification of facts. Field reporters were nominated on the basis of recognized involvement in oncology practice and, in many cases, in leadership positions in oncology or in oncology pharmacy in their country. The methodology incorporated measures to minimize error, including multiple reporters and cross-checks between reporters, and a process of open peer-review. Cross-checking between reporters was not possible in 13/21 Western and 12/27 Eastern European countries where submissions were received by one reporter, in which case additional verification was only possible in the open peer-review process.

Regarding the scale for out-of-pocket cost, the cost bracket of ‘<25% cost’ represent a heterogeneous range between, at the low end, some that are largely symbolic and some that have an annual capitation (Switzerland) and some, at the high end, that represent a very heavy economic burden on patients and their families.

The contents of the discussion regarding public policy implications of the findings (Below) are the independent opinions and conclusions of the author/investigators whose’ conflicts of interest are disclosed, and they should not be imputed to necessarily represent the opinions of the collaborating organization that have supported this study.

### shortages as a barrier to access

Our study found that even some classical, low-cost, anticancer medicines, e.g. tamoxifen and cisplatinum, were not always routinely available largely due to manufacturing and distribution issues. This has been confirmed in a recent study by the European Association of Hospital Pharmacists which found that such shortages often cause problems in availability that last for weeks [24]. It is speculated that there are not enough manufacturers producing certain medications, or companies marketing and distributing them due to a lack of financial motivation to produce these low-profit margin medicines. Consequently, medicines in short supply may also be preferentially distributed to countries which offer higher profit opportunities. Taken together, these concerns prompted the EMA to publish a paper on medicinal product supply shortages caused by manufacturing issues [25] and to take active measures to prevent some of the consequences [26]. A recent analysis of the problem highlighted that Europe is far behind the USA in terms of a standardized and transparent reporting mechanism about the reasons for medicine shortages [18] and consequently the link between shortages market attractiveness, and market availability remains speculative.

Governments and the public sector also have critical responsibilities to establish and maintain effective supply mechanisms for essential medications [27, 28]. The observation of instances of pervasive supply problems across many agents in a single country, as was observed in several Eastern European countries, suggests governance issues as a contributing factor.

### expensive anticancer medications and inequity of access

#### significance

The most striking examples of inequality in anticancer medicine access and availability across Europe were found around new and very expensive anticancer agents used in the noncurative setting. The significance of this finding is a matter of divergent approaches. Some may argue that expensive, noncurative therapies should not be a priority for national cancer control planning in the resource-constrained environment of Europe's middle-income countries with low willingness to pay thresholds. In contrast, the EU, in its aspirational documents, has repeatedly expressed a commitment to improving the equity of access to healthcare services across Europe [16, 17] but without substantive recourse to addressing the economic implications of these aspirations. ESMO has developed a nuanced approach emphasizing the role of Health Technology Assessment (HTA) processes and the need to confront the economic implications of high-cost medications on sustainability. The ESMO vision statement for 2020 states: ‘Government authorities must increasingly seek a balance between treatment costs and clinical benefit when assessing reimbursement policies. Ensuring sustainability of, and access to, optimal cancer care for all patients is essential’ [29].

#### economic factors limiting the possibility to subsidize or reimburse all licenced medications

Since many healthcare systems across Europe are underfunded and relatively fragile [30], cost-effectiveness, affordability and sustainability are now critical issues. While these issues are affected by other factors including price markups by wholesalers, institutions and doctors, as well as the rapidly increasing costs of other nonmedical technologies [31] and structural problems in public financing of health care in general and of cancer care more specifically [11, 32], the issue of delivering affordable medicines with a focus on the price, cost and value of new medicines is at the heart of the public policy issues for accessibility, availability and affordability. This assertion holds true irrespective of improvements in the structure of healthcare systems and better public funding.

#### factors contributing/driving the high pricing

Manufacturers pricing for medications are strongly influenced by Medicare laws in the USA (the largest market) which compel Medicare (or the private insurance plans that provide prescription drug coverage under Medicare ‘Part D’) to provide all FDA-approved cancer medications at the manufacturers' list price and without price negotiation [1, 8, 33–35]. This suspension of market forces has contributed to the disconnect between the cost of medications and healthcare outcomes that they deliver [1, 8, 36–38]. International reference pricing, whereby countries negotiate local pricing based on prices in other countries, incentivizes global manufacturers to price new medications as high as the US market will bear and to maintain other international prices within a narrow range to avoid a downward spiral through the mechanism of reference pricing [34, 39–41]. In addition to international reference pricing, most European countries also employ some forms of price negotiations [34, 39–42]. However, the negotiating power of small and lower income countries is limited, and consequently, affordability tends to be negatively correlated with market size and per capita GDP [39–41].

#### the scope of the price problem

Researchers from the UK reported that in the past 15 years the average cost of a course of therapy with a new anticancer agent has increased almost 450%, and the average duration of benefit delivered by these medications has increased by only one-tenth of that amount [43]. Indeed, the progressive increase of medication prices over the past 15 years has made the oncology sector the most profitable sector in the pharmaceutical industry [8, 44, 45] at a time when the pharmaceutical industry has become the most profitable of the main industrial sectors in the USA and Europe [46, 47]. These considerations underscore concerns expressed by some critics of these pricing practices as ‘profiteering’ [1, 2, 8, 38, 48, 49].

#### economic and ethical imperative for change

There is broad consensus that the current pricing structures are excessive and unsustainable and that there is a need for a paradigm change that will enhance affordability and augment the relationship between price and healthcare outcomes while maintaining adequate incentives to capital investment, research and development [1, 8, 33, 37, 50–52]. For newer biological and molecular targeted agents to be part of the solution for better outcomes, and not part of the problem of inequity in care, there needs to be a radical rethinking of the ‘business to bedside model’ for new medicines in cancer. Europe must re-establish normative ethical boundaries which place medicines as part of a fiduciary relationship of beneficence, nonmaleficence and justice [53–55], something that pure business ethics does not do [56, 57]. This ethical approach has been the basis for public campaigns to address high medication costs [52, 58–60].

#### normative approaches to reduce the prices of medication

Advocates of ‘just pricing’ propose a price structure that reflects the magnitude of patient benefits (value) and that ensures ‘reasonable’ profitability and ‘adequate’ incentives for private sector research and development [1, 33, 36, 38, 52, 59, 61]. However, this requires Europe to adopt and accept value-based pricing (VBP) [1, 50, 62]. Health technology assessment authorities, who have responsibility for making decisions regarding medication reimbursement, can use VBP to bridge science and policy. Based on resource allocation considerations reflecting societal values and resources, HTAs in individual countries can fix the price they are willing to pay for each QALY (for example, \$50–100 000 per QALY) or for each level of clinical benefit [63] as has been well modeled by The National Institute for Health and Care Excellence (NICE) in the UK [64].

Negotiated risk sharing is also becoming increasingly popular and may offer middle-income European countries another mechanism for accessing new and expensive agents. The payer and manufacturer agree on a ‘pay for performance’ market structure where the price level and/or nature of reimbursement are related to the actual future performance of the medication [65, 66]. Thus, in return for a guarantee of efficacy, a payer will add a new product to its formulary that it would not have added otherwise. Like VBP, negotiated risk sharing also aligns financial incentives with improving health outcomes. For example, the UK National Health Service implemented an arrangement to provide gefitinib for patients with locally advanced or metastatic non-small-cell lung cancer at a single-fixed cost of £12 200 per patient responding after 3 months of treatment [67]. A recent review identified 148 risk sharing arrangements, including 77 for oncology medications, mainly in Western Europe but also in Australia, Brazil, Israel and China [65]. While the mechanisms for this have been well developed, e.g. by NICE, it is most effective in countries or regions where there is a central purchaser in a large volume economy, which presents a major challenge to many European countries with different and mixed health economies [39–41].

Another mechanism that could assist with access is differential pricing, whereby there is adaptation of prices to the economic resources of the country [34, 39, 68]. Effective application of this approach requires identification of those countries who otherwise could not afford the medication and also the ability to restrict parallel export from low-priced markets to high-priced markets (market segmentation), both of which have proved challenging in practice. This model has mainly applied to antiretroviral and antiviral medications with fewer examples involving antineoplastic agents. Roche has developed a ‘second brand strategy’ for emerging markets and in India for Herceptin (trastuzumab) and Mabthera (rituximab), both of which were recently included in the 2015 update of the WHO Model List of Essential Medicines [23]. For least developed countries, Glaxo Smith Kline has capped the prices of its patented oncology medicines at no >25% of prices in the UK [69], but this arrangement does not apply to middle-income countries of Eastern Europe.

#### options of last resort

These issues are substantial, and without suitable EU-wide resolution, it is conceivable that European countries may start to undertake more punitive measures, either through capitated budgets for anticancer medications (whereby beyond a capitated budgetary allowance for this purpose some expensive medications will not be available) [28, 70] or by challenging patent monopolies [71–74]. The Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreements of the World Trade Organization has provisions for compulsory licensing as an option of last resort after attempts to negotiate a voluntary licence on reasonable commercial terms have failed [68, 75–78], which has infrequently been invoked for cancer medications. Thailand issued compulsory licensing of docetaxel, letrozole, erlotinib and imatinib in 2008 [68, 78]. In India, local precedent was set in 2012 when a compulsory licence was issued for Nexavar (sorafenib; Roche) allowing a local producer to sell it at 3% of the list price [78–80].

### conclusions

There are disparities in the formulary availability, out-of-pocket costs to patients and actual availability for many anticancer medicines in Europe. Disparities are less among anticancer medicines included in the WHO Model List of Essential Medicines and are most profound in incurable diseases where gains in improved patient outcomes are dependent on the availability of expensive anticancer agents where major differences were seen in availability and in out-of-pocket costs of these medications in the economically less well-developed countries of Europe. In our assessment, based on the findings of this study, the cost of anticancer medications is a major contributing factor contributing to these disparities in Europe, it is also disturbing to see that low-cost medicines, included in the WHO Model List of Essential Medicines, are not universally accessible.

Providing equal access to cancer care in Europe cannot be achieved without addressing these issues. We applaud ESMO on the appointment of a working group, to be led by Prof. Josep Tabernero, to address the critical issue of medication costs, affordability and accessibility. The findings of our study underscore the importance of this task, which we recognize will not be an easy one. The stakes are high and progress to address these issues will require a courageous re-evaluation of long-held vested interests and the constructive cooperation of all critical stakeholders, including the pharmaceutical industry and their investors, governments and their regulatory agencies, third-party payers, professional organizations and patients. Future high-resolution studies of specific European countries should be undertaken to provide the necessary macro- and microeconomic intelligence to support evidence-based policymaking.

## funding

This project was funded by ESMO (no grant number applied).

## disclosure

A.E. currently conducting research sponsored by Roche, GSK, Novartis, Astra Zeneca, Celltrion and Apotex Inc. All remaining authors have declared no conflicts of interest. N.C. received funding from ESMO for project design and development, data processing and writing the manuscript.

## acknowledgements

The authors wish to acknowledge the feedback and input of representatives of the collaborating partner organizations who critically reviewed earlier versions of this manuscript. Acknowledgement also goes to the support and contributions of the ESMO Executive Board, who authorized funding of this project, and the logistic and organizational support provided by ESMO Staff and in particular Gracemarie Bricalli, project manager, with the assistance of her colleagues Tanya Kenny, Nicola Latino and Marina Cogo. We also thank Gilberto de Lima Lopes, Daniel Goldstein, Ian Haines, Leonard Saltz and Elizabeth De Vries who reviewed and provided feedback on earlier versions of the manuscript. The authors also thank and acknowledge the wonderful field reporters who completed that survey and peer-review. In supplementary Appendix SI, available at Annals of Oncology online, we have listed the field reporters who have agreed to place their names in this publication and we also thank those who wished to remain anonymous.

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