Author byline as per print journal: Brian Godman^1,2,3,4, BSc, PhD; Andrew Hill⁵; Professor Steven Simoens⁶, MSc, PhD; Amanj Kurdi^1,7, BSc, PhD; Jolanta Gulbinovič⁸, MD, PhD; Antony P Martin^2,9; Angela Timoney^1,10; Dzintars Gotham¹¹, MBBS; Janet Wale¹²; Tomasz Bochenek¹³, MD, PhD; Celia C Rothe¹³; Iris Hoxha¹⁴; Admir Malaj¹⁵; Christian Hierländer¹⁶; Robert Sauermann¹⁶, MD; Wouter Hamelinck¹⁷; Zornitza Mitkova¹⁸; Guenka Petrova¹⁸, MPharm, MEcon, PhD, DSci; Ott Laius¹⁹; Catherine Sermet²⁰; Irene Langer²¹; Gisbert Selke²¹; John Yfantopoulos²²; Roberta Joppi²³; Arianit Jakupi²⁴; Elita Poplavska²⁵, PhD; Ieva Greiciute-Kuprijanov²⁶; Patricia Vella Bonanno¹, BPharm, MSc, PhD; JF (Hans) Piepenbrink²⁷; Vincent de Valk²⁷; Carolin Hagen²⁸; Anne Marthe Ringerud²⁸; Robert Plisko²⁹; Magdalene Wladysiuk²⁹; Vanda Marković-Peković^30,31, PhD; Nataša Grubiša³²; Tatjana Ponorac³³; Ileana Mardare³⁴; Tanja Novakovic³⁵; Mark Parker³⁵; Jurij Fürst³⁶; Dominik Tomek³⁷, PharmD, MSc, PhD; Mercè Obach Cortadellas³⁸; Corinne Zara³⁸; Maria Juhasz-Haverinen³⁹, MScPharm; Peter Skiold⁴⁰; Stuart McTaggart⁴¹; Alan Haycox¹, PhD

Introduction: There are appreciable concerns among European health authorities with growing expenditure on cancer medicines and issues of sustainability. The enhanced use of low-cost generics could help. Aims: Consequently, there is a need to comprehensively document current and future arrangements regarding the pricing of generic cancer medicines across Europe, and whether these are indication specific, as well as how this translates into actual prices to provide future direction. Methodology: Mixed-method approach with qualitative research among senior health authority personnel and their advisers. Quantitative research via health authority databases to ascertain current prices for oral cancer medicines that had lost their patent and the influence of population size and economics on prices. Results: Twenty-five European countries participated. The research found the following issues: (a) variable approaches to the pricing of generic cancer medicines, which will continue; (b) no concerns with substitution for oral generic cancer medicines; (c) substantial price reductions versus originators for generic capecitabine (up to -93.1%), generic imatinib (up to -97.8%) and generic temozolomide (up to -80.7%). Prices for oncology medicines are not generally indication specific, and are not affected by population size although influenced by pricing approaches. There have also been price increases for some non-patented cancer medicines following manufacturer changes although now stabilizing. Conclusion: The considerable price reductions seen for some generics means health authorities should further encourage the use of generic oncology medicines when they become available to fund increased volumes and new valued cancer medicines. Countries are also starting to address price increases for generics following changes in the manufacturer.

Submitted: 5 February 2019; Revised: 14 March 2019; Accepted: 20 March 2019; Published online first: 2 April 2019

Introduction

Despite the limited health gain for most new cancer medicines, their prices have increased appreciably in recent years [1–7]. This is reflected in the price per life year gained for new cancer medicines rising fourfold during the past twenty years after adjusting for inflation [2, 8]. Typically, prices for new cancer medicines are now approximately 6,000 to 9,000 Euros/patient/month and growing [1, 5, 9], with typically higher prices for new cancer medicines in the US versus Europe. As a result of rising prices for new cancer medicines, as well as increased prices for patented cancer medicines [5, 10–12], coupled with the increasing prevalence of cancer [1, 13], spending on cancer medicines in Europe has more than doubled in recent years, rising from Euros 8 billion in 2005 to Euros 19.1 billion in 2014 (at current prices) [14].

As a result, medicines for oncology now dominate pharmaceutical expenditures in developed markets, with projected worldwide sales for oncology medicines in 2017 ranging from US$74 to US$84 billion [15]. Overall, total worldwide sales of oncology medicines are expected to reach US$112 billion (Euros 91 billion) per year by 2020 [16]. Further growth is expected after this with cases of cancer worldwide likely to rise to 21.4 million per year by 2030 [1, 13] coupled more with than 500 companies actively pursuing new oncology medicines in over 600 indications, and looking to benefit from their investment [17]. The cost of cancer care also currently accounts for up to 30% of total hospital expenditure across diseases among European countries, and this is also rising with the launch of new premium-priced cancer medicines [14, 18].

Increasing prices for new cancer medicines, combined with increasing prevalence rates, is putting considerable strain on patients to access cancer treatments and healthcare systems to fund them [19–23]. High reimbursed prices for new cancer medicines certainly in Europe have been enhanced by the emotive nature of cancer, capturing public, physician, and political attention [13, 24–27]. If these trends with new cancer medicines continue, there is a real risk that universal healthcare across Europe will become unsustainable, which will not be in the best interest of any key stakeholder group. Initiatives among European health authorities to help fund future cancer treatments, including new valued high-cost medicines, include encouraging greater use of generic cancer medicines when they become available [12, 26]. This is especially important given the increasing number of cancer medicines that are now out of patent [28]. Initiatives to enhance greater use of generic cancer medicines include encouraging International Nonproprietary Name (INN) prescribing, financial incentives to enhance the prescribing and dispensing of generics versus originators, as well as compulsory generics substitution [29–38]. INN prescribing is supported by multiple publications showing no difference in effectiveness and safety between generics and originators across a range of disease areas including oncology medicines [28, 39–44]. There have though been concerns with generic imatinib due to different polymorphic forms between the originator and generics as early small scale studies suggested differences [45]. However, later studies involving more patients showed no difference in outcomes between generics and originators of imatinib [45, 46], and, typically, no substantial evidence that generic imatinib is less effective than the originator [47].

In general, prices for generic medicines in Europe are 20% to 80% below originator prices; however, some generics can be priced as low as 2% to 4% of the originator price before the patent was lost [48, 49]. As a result, substantial differences can occur in the prices of generics across Europe [37, 50, 51]. Overall, low prices can potentially be achieved for generic cancer medicines because of the low cost of goods that have been reported at just 1% or more of originator prices for some new cancer medicines [52, 53]. These low cost of goods have already resulted in considerable discounts for generic imatinib across countries versus pre-patent loss prices [54, 55]. However, this is not universal. For instance, in China, generic imatinib is only 10%–20% below originator prices although generic capecitabine is 50% lower than originator prices [56]. There have also been low prices for generic versions of paclitaxel in Europe at just over 1% of originator prices [57]. Docetaxel also has a low price in some European markets enhanced by an appreciable number of generic versions available [26]. Having said this, changes in the manufacturer have resulted in the prices of some low volume old anticancer medicines rising appreciably among European countries including Italy and the UK [58]. However, pharmaceutical companies are now being fined for such behaviour, e.g. Euros 5.2 million for Aspen in Italy for price increases for some of its anticancer medicines, with ongoing investigations and initiatives across Europe to address this [59, 60].

In some European countries, there have also been issues regarding the prescribing of certain generic medicines where there are different indications, one of which is still patent protected. This was the case with pregabalin for the treatment of neuropathic pain as opposed to epilepsy [61].

There have also been concerns with drug shortages if the prices of medicines including generics become too low, which is already happening for certain parenteral medicines [62]. However, these concerns have to be balanced against the increasing availability and use of low-cost generic medicines to release resources to fund increased cancer care including new innovative medicines, reducing patient co-payments where these exist, and stimulating innovation [13, 48, 63–65].

Consequently, there is a need to document current regulations surrounding the pricing of generic oral anticancer medicines across Europe, and their impact on subsequent prices, as well as issues regarding prices of medicines once one indication loses its patent but not the others. As a result, the aims of this paper are multiple. The primary aim is to document current arrangements for the pricing of oral generic medicines across Europe and whether there are any differences in pricing policies for generic cancer medicines versus those for other disease areas. This is important to maximize savings following generics availability as we do see differences in reimbursement decisions for new medicines for cancer versus those for other disease areas [27, 66]. Secondly, to investigate what happens to the prices of oral cancer medicines if one indication loses its patent but not the other indication(s) since indication-specific pricing will undoubtedly reduce potential savings following generics availability, and, as mentioned, there were issues with the prescribing of pregabalin across indications when the first indication lost its patent [61]. Thirdly, to investigate how payers and their advisers envisage developments in the pricing of oral generic medicines for cancer as more cancer medicines lose their patents. Fourthly, to assess whether health authorities have any concerns with patient safety when prescribing oral generic cancer medicines similar to the situation with medicines with a narrow therapeutic index, such as lithium and certain medicines for epilepsy [67–69]. Fifthly, to review current prices for a number of oral cancer medicines across Europe where generic versions are available in all or some of the countries. This will also include an evaluation of prices over time to fully assess the impact of the different pricing arrangements for generic cancer medicines across Europe since we are aware that prices of generics can vary substantially across Europe due to different policies [26, 37, 48, 49], and that Central and Eastern European (CEE) countries are likely to have generics earlier [70]. Sixthly, to assess whether there are any differences in the prices of generics by population size and geography (CEE versus Western European countries) as there have been concerns that countries with small populations, and hence lower economies of scale, may have difficulty negotiating low prices for medicines [71] ; however, published literature has not found to be the case [31, 72]. Countries with greater economic power may potentially be able to negotiate lower prices for generics, and we will also investigate this. Lastly, as mentioned, prices of some old low volume anticancer medicines have risen among European countries in recent years with changes in the manufacturer [58], and we will assess the impact of any changes in manufacturers on subsequent prices, and the likely future direction.

We developed a number of hypotheses for the different aims. These include:

• there will be no difference in the pricing of generics for cancer medicines versus generics for other disease areas and no changes in the short term with pricing regulations for generics
• there may be differences in the prices of cancer medicines for different indications similar to pregabalin
• there will be no safety concerns with oral generic cancer medicines and so no concerns with substitution
• there will be substantial price reductions for oral generic cancer medicines similar to other generic medicines; however, prices will vary considerably across Europe similar to other generics
• population size and economic power will make limited difference on possible prices for oral generic cancer medicines, with prices mainly governed by the pricing policies in individual countries.

We believe that this is the first time that such comprehensive research regarding the regulations surrounding the pricing of oral cancer medicines, and their influence on subsequent prices, has been undertaken across Europe. Consequently, we believe the findings will inform future discussions within and between European and other countries regarding the pricing of oral generic cancer medicines now and into the future. In addition, we aim to stimulate discussions regarding subsequent prices and/or discounts for still patented oral cancer medicines that used off-patented products as their comparator during pricing negotiations. As a result, help with issues of affordability and sustainability of medicine use in the future in this high priority disease area.

When we refer to ‘generics’, we mean the chemical entity (INN). This study also includes imatinib, a comparatively newer anticancer agent, which is treated similarly to other oral generic cancer medicines. Biosimilars of originator biological medicines are regulated by a different framework, and incentives to increase their use are different [73]. Consequently, we will not be discussing biosimilars.

We have chosen to concentrate on Europe in view of the high use of generic medicines in this region. There are also different approaches to the pricing of generics among the various countries, as well as an appreciable number of existing initiatives to enhance the prescribing of generic medicines.

Methodology

A mixed method approach was employed including both qualitative and quantitative research to meet the study objectives, and included 25 European countries, see Box 1.

Box 1: European countries taking part in the study Albania, Austria, Belgium, Bosnia & Herzegovina (Republic of Srpska), Bulgaria, Cyprus, Estonia, France, Germany, Greece, Italy, Kosovo, Latvia, Lithuania, Malta, The Netherlands, Norway, Poland, Romania, Serbia, Slovenia, Slovakia, Spain (represented by pricing data from Catalonia), Sweden, and the UK (represented by pricing data from Scotland with tariff prices consistent across the UK)

This appreciable number of European countries fully encompasses differences in geography, population size, gross domestic product (GDP) per capita, pricing approaches towards generics as well as different approaches to the financing of healthcare [30, 70, 74]. Countries were also broken down into CEE and Western European countries based on the Organisation for Economic Co-operation and Development (OECD) definition [75] to ascertain any differences in the pricing of oral generic cancer medicines based on population sizes and market power.

Qualitative interviews were undertaken with senior personnel within health authorities including heads of pricing and reimbursement of medicines as well as their advisers and a limited number of academics with expertise on national pharmaceutical issues and other key issues among European countries. The involvement of these senior level personnel in the qualitative interviews, and their involvement as co-authors, is seen as very important to enhance the accuracy, robustness and insight of the replies as there have been concerns when such approaches are not used [76, 77]. The co-authors were either identified via the Piperska group [78, 79] – a multidisciplinary network of professionals with interest in the quality use of medicines – or had been previous co-authors on similar pan-European projects involving generic medicinal products [29, 80–82]. We have successfully used this approach in other key areas [30, 61, 70, 73, 74, 80, 81, 83].

The qualitative questions to address the identified objectives included:

• Current regulations for the pricing of generics in their country and whether there are any differences for oral generic cancer medicines versus those for other disease areas
• Whether there are any concerns with the substitution of any of the selected oral cancer medicines or other oral cancer medicines similar to the situation with lithium and some medicines for epilepsy?
• What is the current situation for the pricing of multiple sourced medicines for cancer if one or more indications are still patent protected building on the experiences with pregabalin?
• Any likely future changes in the pricing of oral generic medicines for patients with cancer?

If applicable, pricing policies for generics were broken down into three principal groups to aid comparisons. This builds on previous publications that have used this approach [84–87], and include:

• prescriptive pricing policies (price regulated market) with established percentage reductions for successive generics
• market forces (free market) where there is typically free pricing for generics with market forces helping to drive down prices
• mixed approach (combination) including prescriptive approaches, market forces and other mechanisms including external reference pricing among selected European countries as external reference pricing is common across Europe.

Health authority and health insurance company databases were used for the quantitative research apart from Greece and Serbia where commercial sources were used. The information within these databases is robust as they are typically used to trigger payment to pharmacists. In addition, the databases are regularly audited, and cover the whole country rather than a sample of pharmacies as seen with commercial databases. We have used this approach before when conducting research on prices and utilization of generics, originators and patented products within a class or related class [30, 49, 70, 72, 80–82, 88].

The oral cancer medicines selected for the quantitative research were busulfan (L01AB01), capecitabine (L01BC06), chlorambucil (L01AA02), cyclophosphamide (L01AA01), flutamide (L02BB01), imatinib (L01XE01), melphalan (L01AA03), methotrexate (L01BA01), and temozolomide (L01AX03) [89]. These oral cancer medicines were chosen to provide a range of medicines for use across different cancer types, with typically multiple indications, covering the oral cancer medicines listed in the World Health Organization (WHO) essential medicines list, and exhibiting varying timings regarding the loss of patent, building on previous publications [55]. Oral medicines, such as gefitinib, sorafenib, sunitinib and tioguanine were not included as there appeared to be no generics yet available for these oral cancer medicines even among the selected CEE countries at the time of the study. The (non-) tyrosine kinase inhibitors are a particular case as there are typically multiple indications as well as potentially different dates for patent loss across countries [90].

Since the perspective of this study is that of health authorities, reimbursed prices were principally chosen for comparative purposes rather than total prices, which include patient co-payments. Reimbursed prices can include prices after deducting legally mandated discounts; however, this is unlikely for generic medicines. In a minority of countries, e.g. Kosovo, procured and total prices were used as reimbursed prices were unavailable. In Italy and Norway, reimbursed prices were also listed but the medicines are typically dispensed in hospitals where further confidential discounts are provided. However, since these discounts are confidential, we could only report ambulatory care prices. Furthermore, in some countries, prices did not include VAT and/or pharmacy margins, e.g. Malta, The Netherlands and the Republic of Srpska. However, this was not seen to have an appreciable impact on the analyses since percentage reductions were typically used for comparative purposes to assess the influence of different policies. In addition, the prices of generics at least initially in a number of European countries are based on percentage reductions from pre-patent loss originator prices [30, 70]. We have successfully used this approach in a number of previous publications [30, 70, 74, 80, 84].

We are conscious that we used prices from Scotland rather than the UK as a whole. However, there are no differences in prices across the UK with reimbursed prices in ambulatory care based on the tariff price coupled with free-market competition, which leads to further price reductions over time. Similarly, no differences are envisaged in generic and originator drug prices in ambulatory care in Catalonia versus Spain as a whole. However, we acknowledge that there will be differences in hospital prices across Spain through variations in discounts and managed entry agreements between the different regions [91].

Prices were collected over a period of time between 2013 and 2017, based on the unit, e.g. tablet strength, for the different originators and the cheapest generics substitute unit available, especially for branded generics, as opposed to defined daily doses (DDDs). Unit strength was chosen as generally there are no DDDs for oral cancer medicines in view of typically a number of indications for each molecule [89]. The documented prices for each year between 2013 and 2017 were the last available price for that year, e.g. October to December if prices are adjusted every three months or December if prices are adjusted monthly. The years were chosen to assess the extent of any price changes in recent years especially given recent price increases for some off-patent medicines.

The actual unit strength chosen for comparative purposes reflects the most used strength in a number of European countries, although we recognize that there may be different strengths available in some countries. In addition:

• If no generic drug was available in a country, this was recorded as NA (not available).
• If the generics were not available in the suggested strength – but were available in different strengths along with the originator – then the strengths were typically recorded to track particular generic drug prices over time and in relation to the originator. This may mean we could not undertake comparisons between countries in all cases; however, this was a secondary consideration.
• If there were different pack sizes for the generics versus originators in the stated strength, the pack size chosen was the size that gave the lowest price per unit during the year and again a note was made of this practice.
• If the generics were only available in liquid form but the originator was still available as a tablet, we stated that the generic drug was not available as a tablet (NA) and just recorded the originator details in the spreadsheet. However, the strength of the generic liquid formulation and its price over time were recorded separately on an MS Excel sheet to see if this changed over time. This would be commented on if pertinent.

Initially, prices were documented in the country’s currency if this was not Euros. Subsequently where relevant, prices were converted to Euros for the purposes of comparison based on current exchange rates and validated with the co-authors to enhance the robustness of the findings, see Table 1A in the Appendix.

Table 2A in the Appendix contains details of the population sizes and the breakdown of countries into three groups for analysis purposes (small, medium and large). Countries with populations under three million were described as small, those with populations between three and 16 million as medium, and the remainder as large to produce three roughly equal groups although recognizing that more countries were in the ‘small’ category than in the others.

Statistical tests were performed to ascertain any trends in prices across countries as well as any difference in price reductions over time as a result of the different approaches towards the pricing of generics across Europe. The significance threshold was set at p > 0.05. Statistical tests were also run to check whether prices were influenced by population size as this has been a concern in the past. However, we did not have enough variables to perform any multivariate analyses as there are not enough specific measures in each European country that had been initiated to control the price of generic cancer medicines which could be used as a yes/no variable. We have though collated the impact of the different pricing approaches for generic medicines across Europe as one of the principal objectives of this paper was to document these and their influence on subsequent prices for oral generic cancer medicines.

No analysis was made regarding the impact of volumes on generic drug prices as seen in other studies because this was not a focus of the paper [92]. This will be followed up in future studies. Potential savings from the increased utilization of generic medicines for cancer over time will also form a separate project building on previous calculations [93].

Results

In line with the objectives of this paper, we will first report the findings from the qualitative research. This will be followed by the findings from the quantitative research.

Regulations surrounding the pricing of generics including those for cancer across Europe
Regulations for the pricing of generics generally and for oral cancer medicines including likely changes in the short term
As previously seen, there were differences in the approaches to the pricing of generics among the various European countries, see Table 1, which could again be categorized under three broad headings. These are: (i) prescriptive pricing approaches; (ii) market forces, and (iii) and a mixture of the approaches.

As shown in Table 1, there were no differences in the pricing approaches for generic oral medicines for oncology compared with those for other disease areas, see Table 1, apart from the fact that in some countries these cancer medicines were dispensed in hospitals, which could include additional discounts that are typically confidential. This is important given the considerable savings that can be achieved with the introduction of generics, see Table 2.

Pricing of oral cancer medicines if one indication has lost its patent
There were generally no issues with the pricing and usage of oral generic cancer medicines once one indication had lost its patent but not the other indication(s), see Table 1; however, this was not universal. There is similar to the situation in Germany once the first indication for a multiple-sourced product has lost its patent [61], i.e. the generic medicine can be prescribed across all indications at the discounted price versus the originator. However, this is different to the situation that existed with pregabalin among a number of European countries where the generics could only be prescribed for epilepsy and the originator must be prescribed and reimbursed accordingly for neuropathic pain [61].

This situation is encouraging for maximiẕing savings following generic drug availability given the considerable savings that can be achieved with the introduction of generics, see Table 2, and will be closely monitored in the future. This includes procured medicines for distribution in hospitals.

Substitution of oral cancer medicines and initiatives to encourage their prescribing
It was also encouraging to see that once generics became available, there were no concerns with substitution with the selected oral generic cancer medicines, see Table 1. This is similar to the general situation for cancer medicines [28]. Consequently, originators can be substituted with generics without compromising care. This is again important for maximizing savings once generics become available.

Initiatives to encourage the prescribing of generics in preference to originator cancer medicines among the various European countries, see Box 2, were similar to those for generic medicines in general.

Box 2: Initiatives across Europe to enhance the prescribing of generics versus originators The cheapest priced medicine is the first alternative for patients (Albania) Additional patient co-payments to cover any price difference if the patient prefers an originator versus a generic drug, e.g. Bulgaria, Latvia, Serbia, and Slovenia Incentives for physicians to prescribe generics rather than originators, e.g. Austria Incentives for pharmacists to substitute with a generic drug if an originator is prescribed, e.g. France Encouraging INN prescribing, e.g. Estonia, Lithuania, Romania and the UK. INN: International Nonproprietary Name.

Price reductions with generics over time and with originators, as well as the influence of population size and market forces
Prices for originator 400 mg imatinib were similar in Western European countries in 2015 before generic drug availability, see Figure 1. Generic imatinib was already available in CEE countries, e.g. in Albania, Estonia, Latvia, Lithuania, Romania, Serbia and Slovakia, on or before 2013, and in Poland and Slovenia in 2014. Generic capecitabine and flutamide were already available in a number of Western European countries in 2013. The other three oral anticancer medicines were already available as generics among Western European countries before 2013.

As expected, there were differences in the prices of the generics for capecitabine (500 mg), flutamide (250 mg), imatinib (400 mg) and temozolomide (20 mg and 250 mg) in 2017 among the European countries where these generics were available, see Table 3, reflecting differences in the approaches to the pricing of oral generics among the various European countries, see Table 1.

There were no differences in the prices of capecitabine (500 mg), flutamide (250 mg), imatinib (400 mg) and temozolomide (20 mg and 250 mg) when the countries were broken down into small, medium or large populations, see Table 2A, apart from generic imatinib for European countries with large populations, i.e. capecitabine (p = 0.372 for medium and p = 0.100 for large), flutamide (p = 0.700 for medium and 0.385 for large), imatinib (p = 0.249 for medium and p = 0.037 for large), temozolomide 20 mg (p = 0.764 for medium and p = 0.085 for large) and temozolomide 250 mg (p = 0.951 for medium and p = 0.105 for large). Prices for generic capecitabine (p = 0.007), generic imatinib (p = 0.015) and temozolomide 20 mg (p = 0.015) were though typically appreciably higher when combined among Western European countries compared with CEE countries. However, this was not the case for flutamide 250 mg or temozolomide 250 mg. This will change for generic imatinib as prices fall among the large Western European countries over time, e.g. generic imatinib in Scotland by March 2018 was already 89.1% below pre-patent loss prices having only been made available in 2016.

Overall in 2017, the differences in the prices of generics of capecitabine (500 mg), flutamide (250 mg), imatinib (400 mg) and temozolomide (20 mg and 250 mg) among the different European countries, see Table 3, appear to be a reflection of the differences in the country’s pricing approaches towards generics, see Table 1, rather than population size when broken down into small, medium or large, as well as the timing of generic drug availability. These findings are similar to those with generic busulfan, chlorambucil, cyclophosphamide and melphalan, see Table 4, and confirm this trend certainly for oral generic cancer medicines.

There also appears to be no correlation in terms of the price reductions seen for generic capecitabine, flutamide, imatinib or temozolomide in 2017 versus 2013 originator prices with population sizes, i.e. appreciable price reductions over time were not confined to European countries with higher populations, see Table 2. There was also no significant difference in the percentage reduction between Western and CEE countries for capecitabine, flutamide, imatinib or temozolomide.

If anything, there was a greater reduction in the prices of generic capecitabine, see Figure 2, in countries with a mixed approach to the pricing of generics versus those with market forces (p = 0.035) and prescriptive (p = 0.041) approaches.

This was not the case for generic imatinib, see Figure 3, although there was a trend (p = 0.079 for market forces and p = 0.119 for prescriptive pricing approaches). However, this may change as prices of generic imatinib fall in The Netherlands, Spain, Sweden and the UK, e.g. as mentioned generic imatinib in Scotland was already 89.1% below pre-patent loss prices by March 2018 having only been made available in 2016.

Price changes for generics with changes in the licence holder
In recent years, the generic drug manufacturer Aspen has taken over the licence of busulfan, chlorambucil, and melphalan and enjoyed market monopoly, with typically no generics competition, despite the loss of patent protection. Another pharmaceutical company, Baxter, has used a similar strategy with cyclophosphamide. Countries have typically been faced with having to either accept these higher prices or no longer procuring and/or reimbursing these medicines.

Figure 4 depicts current prices per tablet for these four oral generic anticancer medicines (2017) where these are currently listed and reimbursed since not all European countries currently reimburse these four medicines. There were no significant differences in the mean prices for these four anticancer medicines between Western and CEE countries. In the case of busulfan, there was a difference in current prices among European countries, with Western European countries typically having higher prices but this did not reach significance (p = 0.08). Population size again did not appear to influence subsequent prices.

There were appreciable price rises in a number of other European countries following Aspen’s purchase of busulfan, chlorambucil and melphalan from GlaxoSmithKline, see Table 4.

Similar price rises were seen in Germany during this period, for example:

• Busulfan (Myleran – L01AB01): price until 30 April 2012: Euros 29.90 for 25 × 2 mg tablets (Euros 1.196/tablet); thereafter Euros 109.11 for 25 tablets (Euros 4.364/tablet), i.e. a 264.9% increase
• Melphalan (Alkeran – L01AA03): price until 30th April 2012: Euros 42.30 for 25 × 2 mg tablets (Euros 1.692/ tablet); thereafter Euros 93.94 (Euros 3.758), i.e. a 122.1% increase
• Chlorambucil (Leukeran – L01AA02): price until 30th April 2012: Euros 32.74 for 25 × 2 mg tablets (Euros 1.31/tablet; thereafter Euros 80.03 (Euros 3.201), i.e. a 144.4% increase
• With respect to cyclophosphamide, price rises have also been seen among some European countries between 2013 and 2017 following Baxter’s involvement. These include Latvia (34.1%), Norway (44.8%), Slovenia (56.3%), Slovakia (57.0%), The Netherlands (120.5%), Albania (121.1%) and Sweden (135.3%).

Overall there again appears to be no link between prices, geographic region and population size for these four medicines despite previous concerns. If anything, countries with smaller populations, such as Estonia had lower prices than Belgium, Italy and the UK. This appears to be in contrast with previous publications [71], although this is in accordance with previous findings in Lithuania and the Republic of Srpska [31, 72].

The difference in prices of these four molecules between the countries in 2017 may well reflect differences in negotiations when the new company took over the molecules and relaunched them as a new originator at a higher price. Countries such as Estonia appeared successful in negotiating lower price increases for the relaunched medicines versus for instance Belgium, Italy and the UK. However, as mentioned earlier, the company was subsequently fined Euros 5.2 million in Italy for their activities [59]. Currently, Germany has a moratorium law stating that for any price increase, there will be an increase in the mandatory rebate of exactly the same amount as the increase. Effectively, this means that the price paid by statutory heathcare funds for ambulatory care medicines does not change [114, 115]. Legislation is also being introduced in the UK to reduce the price of generic medicines where competition fails to reduce prices and companies are seen to charge the National Health Service (NHS) unreasonably high prices [113]. The Competition and Markets Authority (CMA) in the UK has also provisionally found that two companies broke the law by agreeing not to compete to supply generic hydrocortisone to the NHS driving up annual costs by two million GBP [116]. There are also ongoing deliberations in Europe regarding concerns with appreciable price increases for generics and whether this breaks EU competition rules [60, 117]. In addition, we may see countries combining to form regional co-operations between Member States to further reduce prices where there are concerns with unjustified price rises building on current consortia [118–120]. However, this has to be balanced against issues of future profitability and potential drug shortages with for instance only 75 melphalan tablets dispensed in ambulatory care in Scotland during the study period (SM personal communication), and with just 11 boxes of generic melphalan dispensed in Serbia in 2015.

Discussion

We believe this is the first study to comprehensively research the situation regarding the pricing of oral generic cancer medicines in this high priority disease area. We believe our findings again highlight the differences that are seen in the various approaches to the pricing of generics across Europe, see Table 1, and their subsequent influence on the prices of generics and discounts obtained. These considerable differences are in direct contrast with the more limited differences in prices for on-patent medicines across Europe, especially high cost ones [121], although these can still be considerable [122].

Prices for generic capecitabine, imatinib, and temozolomide 20 mg, were significantly higher when combined among Western European countries as compared with CEE countries. This may reflect greater availability of resources to spend on medicines among Western countries. However, this is not universal as there were no differences in prices between Western European and CEE countries for flutamide 250 mg or temozolomide 250 mg. Alternatively, generics may be available earlier in CEE countries with associated earlier falls in their price as seen with imatinib. As mentioned, generic imatinib in Scotland was already 89.1% below pre-patent loss prices in March 2018 having only been made available in 2016, see Figure 1. Having said this, there were already some appreciable price reductions for these various molecules and strengths among Western European countries comparing generic drug prices in 2017 versus originator prices in 2013, Table 3 and Figure 3. In addition, no overall difference in the price reductions for these molecules and strengths was found for Western European countries combined versus CEE countries combined.

The picture regarding methotrexate is complicated by the use of this medicine for immunological conditions, such as rheumatoid arthritis and psoriasis. This meant that different originator and tablet strengths (2.5 mg or 5 mg) were available amongst the European countries making comparisons difficult. In addition, the considerable time that both the originator and generic methotrexate have been available across Europe meant there were limited price reductions in reality between 2017 compared with 2013 among the various European countries. Consequently, no detailed analysis was undertaken with methotrexate.

The price reductions for capecitabine, flutamide, imatinib and temozolomide that have been achieved in practice, see Table 3, confirm the findings of Hill et al. that the costs of goods for cancer medicines can be very low in reality [52, 53]. This fuels the debate for greater transparency in the pricing of new medicines for cancer when pharmaceutical companies request premium prices especially where there is limited health gain for their new cancer medicines versus current standards.

In view of our findings, we also believe European health authorities, as well as health authorities from other countries, can use these results to reassess their pricing approaches for generics, and the subsequent implications for oral generic cancer medicines, given concerns with the increasing costs of medicines to treat patients with cancer and issues of sustainability [3, 9, 28]. This is already happening, and may well accelerate, especially if issues of access and sustainability of cancer care continue to be priority issues for all key stakeholder groups. For instance, Austria, Lithuania, and Sweden, have recently introduced measures to further lower the prices they pay for generics and this trend is likely to continue, see Table 1. However, this has to be balanced against issues of parallel exports and associated drug shortages if the prices of generics become too low [37, 123], which is depicted in the unavailability of some oral generic cancer medicines in the countries studied. This will be the subject of ongoing research.

Based on our findings combined with the continual pressure on oncology budgets, we would also likely to see countries increasingly reassess the prices of on-patent cancer medicines in their country once the comparator medicine used for pricing and reimbursement negotiations loses its patent [124]. Such activities will be enhanced by the low prices that have been achieved for oral cancer medicines once their patent is lost, see Tables 2 and 3, which will continue.

Encouragingly, we saw no differences in the pricing approaches for generic cancer medicines versus those for other disease areas despite the emotive nature of cancer, and this will continue. This is essential to maximize savings from the availability of generic cancer medicines once available, with ongoing initiatives across Europe to encourage their use where pertinent. Likely, current and future initiatives to enhance the prescribing of oral generic cancer medicines include additional demand-side measures especially among European countries with currently low use of generics versus originators. This could be alongside continued educational initiatives among key stakeholder groups, including patients, where pertinent about the lack of problems with oral generic cancer medicines given there were no concerns with substitution among the European countries surveyed, see Table 1.

We are also unlikely to see major changes in pricing approaches once one indication loses its patent. The situation seen in Germany, as well as initiatives to encourage INN prescribing, helps in this regard. These initiatives are essential in oncology given the growing burden of the cost of medicines to treat patients with cancer across Europe combined with the need to continue to provide universal healthcare. Encouraging greater prescribing of generic medicines will be helped by limited or no fears with substituting generic cancer medicines for originators among physicians and pharmacists. This is unlike a limited number of other disease areas including some medicines for patients with epilepsy as well as lithium for patients with certain mental health conditions [67–69].

If companies continue to purchase the patent for old cancer medicines and other products, and relaunch them at considerably higher prices, there is likely to be co-ordinated activities across Europe to try and address this. We are already seeing companies being fined, e.g. Italy, as well as countries instigating measures to reduce any burden from such approaches as seen currently in Germany and the UK. Such punitive actions are likely to grow in the future if this trend continues. However, this has to be balanced against potential availability especially if only small volumes are being used. This will again be the subject of continuing research.

Conclusion

We have again seen appreciable differences in the regulations surrounding the pricing of generics across Europe, reflected in different reimbursed prices for oral generic cancer medicines. Welcomed from an equity and resource perspective were no differences in the pricing approaches for medicines for cancer as opposed to other disease areas to help maximize savings once generics become available. In addition, the prices of generics, and any difference in the prices of generics in 2017, or price reductions versus 2013 originator prices, did not appear to be influenced by population size. This is also encouraging to maximize savings from the availability of oral generic cancer medicines. The prices of some generics were higher among Western European countries in 2017; however, this could have been influenced by generics being available earlier among CEE countries. There are concerns with some off-patented medicines being relaunched by alternative companies at appreciably higher prices, although there are ongoing steps across Europe to try to address this. These initiatives are likely to grow if this trend continues.

Reassuringly, there are no concerns with substitution of oral generic medicines. In addition, prices were typically similar across indications. Both results are important to maximiẕe savings from generic drug availability once at least one indication loses its patent.

We have tried to reduce limitations with this study by using senior level personnel for the qualitative research as well as health authority and health insurance company databases for the quantitative research. However, we are aware that we did not use reimbursed prices throughout the countries, some prices did not include VAT, and we cannot be sure that the medicines chosen for the research are entirely used for cancer indications. Despite these concerns, we believe the findings of our comprehensive research are robust providing direction not only to key stakeholder groups across Europe but also wider.

Funding

There was no funding for this research and no assistance with the write-up.

Competing interests: Most of the authors work directly for health authorities or health insurance companies or are advisers to them. Professor Steven Simoens has previously held the EGA Chair ‘European policy towards generic medicines’. All the authors have no other conflicts of interest to declare.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

¹Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK
²Health Economics Centre, University of Liverpool Management School, Liverpool, UK
³Division of Clinical Pharmacology, Karolinska Institute, Karolinska University Hospital Huddinge, SE-141 86, Stockholm, Sweden
⁴School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia
⁵Institute of Translational Medicine, University of Liverpool, UK
⁶KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium
⁷Department of Pharmacology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
⁸Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
⁹HCD Economics, The Innovation Centre, Daresbury, WA4 4FS, UK
¹⁰NHS Lothian, Edinburgh, UK
¹¹Independent researcher, Boston, MA, USA
¹²Independent consumer advocate, 11a Lydia Street, Brunswick, Victoria 3056, Australia
¹³Department of Drug Management, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
¹⁴Department of Pharmacy, Faculty of Medicine, University of Medicine, Tirana, Albania
¹⁵University of Medicine, Tirana, Albania
¹⁶Main Association of Austrian Social Security Institutions, Department of Pharmaceutical Affairs, 1 Haidingergasse, AT-1030 Vienna, Austria
¹⁷Statistics Department, APB, 11 Rue Archimède, BE-1000 Bruxelles, Belgium
¹⁸Faculty of Pharmacy, Department of Social Pharmacy and Pharmacoeconomics, Medical University of Sofia, Sofia, Bulgaria
¹⁹State Agency of Medicines, 1 Nooruse, EE-50411 Tartu, Estonia
²⁰IRDES, 117 bis rue Manin, FR-75019 Paris, France
²¹Wissenschaftliches Institut der AOK (WidO), 31 Rosenthaler Straße, DE-10178 Berlin, Germany
²²School of Economics and Political Science, University of Athens, Athens
²³Pharmaceutical Drug Department, Azienda Sanitaria Locale of Verona, Verona, Italy
²⁴UBT – Higher Education Institute Prishtina, Kosovo
²⁵Institute of Public Health & Faculty of Pharmacy, Riga Stradins University, Latvia
²⁶Department of Pharmacy, Ministry of Health of the Republic of Lithuania, Vilnius, Lithuania
²⁷National Health Care Institute (ZIN), 4 Eekholt, NL-1112 XH Diemen, The Netherlands
²⁸HTA and Reimbursement, Norwegian Medicines Agency, Oslo, Norway
²⁹HTA Consulting, 17/3 Starowis′lna Str, PL-31-038 Cracow, Poland
³⁰Ministry of Health and Social Welfare, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
³¹University of Banja Luka, Faculty of Medicine, Department of Social Pharmacy, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
³²Health Insurance Fund of Republika Srpska, 8 Zdrave Korde, 78000 Banja Luka, Republic of Srpska, Bosnia and Herzegovina
³³Agency for medicines and medical devices of Bosnia and Herzegovina, Veljka Mladjenovica bb, 78000 Banja Luka, Bosnia and Herzegovina
³⁴Faculty of Medicine, Public Health and Management Department, ‘Carol Davila’ University of Medicine and Pharmacy Bucharest, RO-050463 Bucharest, Romania
³⁵ZEM Solutions, 9 Mosorska, RS-11 000 Belgrade, Serbia
³⁶Health Insurance Institute, 24 Miklosiceva, SI-1507 Ljubljana, Slovenia
³⁷Faculty of Medicine, Slovak Medical University in Bratislava, Bratislava, Slovakia
³⁸591 Gran Via de les Corts Catalanes, 4a place, ES-08007 Barcelona, Spain
³⁹Stockholm County Council, Stockholm, Sweden
⁴⁰TLV (Dental and Pharmaceutical Benefits Agency), 18 Fleminggatan, SE-10422, Stockholm, Sweden
⁴¹NHS National Services Scotland, Gyle Square, 1 South Gyle Crescent, Edinburgh EH12 9EB, UK

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Appendix

Author for correspondence: Brian Godman, BSc, PhD, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK

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