Scholarly article on topic 'New cancer drugs in Sweden: Assessment, implementation and access'

New cancer drugs in Sweden: Assessment, implementation and access Academic research paper on "Clinical medicine"

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Journal of Cancer Policy
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{"Cancer drugs" / Access / Cost-effectiveness / Pricing / "Regional variations" / "Breast cancer" / Leukaemia / Policy}

Abstract of research paper on Clinical medicine, author of scientific article — Bengt Jönsson, Nils Wilking

Abstract Assessment of value for money of new drugs is an important part in decision-making about the price and use of new drugs. The high prices of many new drugs also means that inappropriate use for patients who gain little or no benefit from the treatment creates a high “opportunity cost” in terms of health losses for other patients, for whom the resources could be better used. Sales of cancer drugs in Sweden have risen sharply over the past decade, but the growth of sales has slowed in recent years. There are significant variations among different health regions in the use of cancer drugs, and these variations have increased over the past 5 years. We discuss the issues involved in applying the principle of cost-effectiveness with examples from breast cancer and leukaemia. The debate surrounding the introduction of cancer drugs is focused on the question of who should be the leader in the introduction process. Our view is that in Sweden, with a regionalised health-care system, decisions must be made where patient and financial responsibility rests, on the county councils. However, there is a need for leadership at the national level for assessment and follow-up. Internationally, secret (undisclosed) rebates, based on what is often a very high list price for the drug, are common. There is no tradition of this in Sweden, and there is resistance to this type of discounting since price control in Sweden should be based on public prices. However, the county councils’ responsibility for the introduction of new cancer drugs allows local agreements to be made, in which price is included as one component, improving access for patients without reducing incentives for innovation.

Academic research paper on topic "New cancer drugs in Sweden: Assessment, implementation and access"

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Journal of Cancer Policy

journal homepage www.elsevier.com/locate/jcpo

New cancer drugs in Sweden: Assessment, implementation and access*

Bengt Jdnsson3'*, Nils Wilkingbc

a Stockholm School of Economics, Stockholm, Sweden b Karolinska Institutet, Stockholm, Sweden c Skane Oncology Clinic, Lund, Malmo, Sweden

ARTICLE INFO

ABSTRACT

Article history: Received 8 August 2013 Accepted 24 January 2014 Available online 30 January 2014

Keywords: Cancer drugs Access

Cost-effectiveness Pricing

Regional variations Breast cancer Leukaemia Policy

Assessment of value for money of new drugs is an important part in decision-making about the price and use of new drugs. The high prices of many new drugs also means that inappropriate use for patients who gain little or no benefit from the treatment creates a high "opportunity cost" in terms of health losses for other patients, for whom the resources could be better used.

Sales of cancer drugs in Sweden have risen sharply over the past decade, but the growth of sales has slowed in recent years. There are significant variations among different health regions in the use of cancer drugs, and these variations have increased over the past 5 years. We discuss the issues involved in applying the principle of cost-effectiveness with examples from breast cancer and leukaemia. The debate surrounding the introduction of cancer drugs is focused on the question of who should be the leader in the introduction process. Our view is that in Sweden, with a regionalised health-care system, decisions must be made where patient and financial responsibility rests, on the county councils. However, there is a need for leadership at the national level for assessment and follow-up.

Internationally, secret (undisclosed) rebates, based on what is often a very high list price for the drug, are common. There is no tradition of this in Sweden, and there is resistance to this type of discounting since price control in Sweden should be based on public prices. However, the county councils' responsibility for the introduction of new cancer drugs allows local agreements to be made, in which price is included as one component, improving access for patients without reducing incentives for innovation.

© 2014 The Authors. Published by Elsevier Ltd. All rights reserved.

Introduction

Assessment of the value and cost-effectiveness of new drugs plays an important part in decisions about the price and the use of such drugs. Equally important is the implementation of these decisions in health care. Only when the drug is used properly is value created. A fundamental problem is that the value of the drug is not fully known at the time the decision is made. The SNS ("Centre of Policy Analysis, Stockholm Sweden") research programme on the value of new drugs has presented a number of studies showing that the drug helped to create substantial value for health, care and society in general ("Vardet av lakemedel"; The value of drugs. SNS Forlag 2013). Such studies provide important background information, but give only partial guidance as to how we can and should manage the introduction and use of new drugs.

* This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Corresponding author. Tel.: +46723985678.

E-mail address: hebj@hhs.se (B. Jonsson).

The majority of new drugs, including those within the cancer field, have limited use and low sales. Only a small number of new drugs have great value, and their sales finance the bulk of investment in research and development. The classification of therapeutic value made by the Haute Autorité de Santé (HAS) in France, for example, shows that less than 10% of all new drugs end up in the highest class of five (high therapeutic value) [1]. A study of drug introductions in Sweden, using a three-level classification, showed that 14% ended up in the highest class (important medical contributions) [2]. Early access to these important drugs is therefore an important goal. Increased requirements for documentation prior to use, to ensure the efficacy and cost-effectiveness of the drug, may seem reasonable to reduce uncertainty. But reducing uncertainty costs both time and money, and one cannot wait until one knows everything. Decisions must be made with some uncertainty about the value of a new drug.

In a much-quoted article, the economist Sam Peltzman analysed drug approval decisions based on information on safety and efficacy. He pointed to the asymmetry of the consequences of early approval or deferring the decision. Future adverse events may lead to criticism of the authority for the decision to approve the drug. However, a delayed introduction of a valuable drug rarely leads to criticism just as harsh. The patients who are missing out on the positive effects of a potentially valuable treatment cannot similarly

2213-5383/$ - see front matter © 2014 The Authors. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/jjcpo.2014.01.003

be identified. The "opportunity cost", to use an economic term, is not possible to observe directly, and there is, as Peltzman pointed out, a risk that there will be a distortion of decisions as a result. Systematic studies of the decisions and continuous assessment of the consequences is the method he assigned to create a more optimal balance, viewed from the perspective of society [3].

Peltzman's analysis focused on the balance between efficacy and side effects. In the 1960s, patients themselves paid almost the entire costs of medicines. Consideration of the cost was outside public regulation. Today, public financing is dominant, and the decision problem is a balance between public spending (subsidies) and value. Reimbursement decisions are also made with uncertainty, but the potential loss to society of a wrong positive decision lies primarily in the loss of money. It can be seen as trivial compared to the loss of health if a new treatment that is potentially valuable is not used. The pressure on approval will obviously be great from potential patients who might benefit from the new drug, especially for severe diseases where potential side effects, relatively speaking, are less of a problem. But as with balancing between safety and efficacy, there is a hidden loss of health, namely health that could be created by using resources for more valuable purposes. The use of costly new cancer drugs on patients who gain little or no benefit from the treatment will give rise to health losses in other areas where resources could be better used. The use of different markers for the identification of patients who are candidates for treatment may reduce the risk of wrong decisions, but this cannot be implemented without costs, and the decisions are often also complicated by more sophisticated diagnostics.

The basis for the design of a rational policy is an understanding of opportunity cost, regardless of whether this is directly visible or not. Systematic analysis of the consequences of the decisions, in terms of costs and effects, is the main tool for assessing the balance to aid decisions. We give examples below of how the calculations have been used to guide decisions on the introduction of new cancer drugs.

A fundamental problem with new cancer drugs is that they are often introduced with relatively great uncertainty about their effects. The launch takes place with data only from patients with disseminated disease and a short life expectancy, and in this population the possibility of effectiveness weighs heavier than the risk of side effects. Trials often use progression-free survival (PFS) as a primary endpoint, which means that the effects on overall survival are uncertain, and in many cases cannot be measured because of patients switching to the studied treatment (cross-over). This is a particular problem for so-called targeted treatments. The basic biological knowledge suggests that it is not reasonable just to block a single target. There are exceptions to this - for example, treatment of CML (chronic myelogenous leukaemia) and HER2-positive breast cancer - but these are not typical. A problem is that many of the new targeted drugs give a rapid and dramatic tumour response in some patients, but the tumour response is very short-lasting.

For the new immunological treatments the problems appear to be the opposite: i.e., we see relatively modest tumour responses, and in some instances initial tumour progression followed by a long period of tumour control, and possibly even cure in a proportion of patients. The practical difficulties of making large and long-term studies often impede a full documentation of the relative efficacy and safety of a drug before a decision on its use is made. It is an important reason why new cancer drugs are introduced with great uncertainty about long-term effects and value.

Thus there is a need for further systematic evaluation when a drug is put on the market. The issue becomes: who will pay for this, especially when the prices are high and expenses can be considerable for an uncertain outcome? The health-care system has the resources and expertise for this, but decisions must be made that

strike a balance between different objectives when the resources are limited.

One option would be to see follow-up studies as further research, funded by special grants from the government as part of the funding for medical research. This in turn requires decisions about how large these funds should be and how they should be distributed, and when funding should be terminated. Another option is to link the payment to the results achieved (known as "pay for performance"), and that pharmaceutical companies and the healthcare system design the studies together and share the costs. A problem with this model is that the outcome may depend on a variety of factors, requiring a close and trusting cooperation between pharmaceutical companies and health-care systems for it to work.

It is also important to remember that a drug does not have a single value, but the value is related to which patients are treated. The value can vary between different types of cancer, the stage of the disease, and in what sequence it is given. Also the value, measured as possible survival benefit, varies with the characteristics of the patient (such as age and co-morbidity). Since the value varies, this also leads to problems of how to determine the price; should an average price be calculated, or should there be different prices for different uses? This leads to a discussion of whether the payment should be tied to the drug itself, or whether it should instead be linked to the patient being treated. In the latter case the payment will be made for a service (such as hospitalisation or outpatient treatment) rather than for a product. That creates opportunities for bundling, i.e. tying compensation to the estimated total of all the costs associated with treatment, such as monitoring, treatment of complications, etc. A new option is a "subscription fee", which means that a clinic pays a flat fee and gets free access to the drug for patients with the approved indication. This is similar to price-volume agreements, where there is a very low extra payment if the agreed volume is exceeded.

Regardless of how "generous" the attitude of the payer decision-maker is, there is a need to monitor what actually happens when the drug is used in clinical practice. Sometimes it is not possible to reproduce the effects observed in the clinical trials that formed the basis for registration. This is because patients in a clinical study differ in many ways from those treated in clinical practice. It is also common that the number of cycles of treatment in clinical practice is significantly lower than that in the clinical study. This means that the effectiveness of the drug is often lower than expected. The opposite may also occur, i.e., that the use in new populations, or in a way different from that in the clinical study, creates better effects and greater value in clinical practice. For example, the use of tamoxifen and trastuzumab in early breast cancer is more cost-effective than using them in disseminated disease. It is therefore important not to stop or delay the introduction of the drug even though we do not have full knowledge of the value of the treatment.

We also see examples of the effect in clinical practice being greater than that observed in clinical studies. Such is the case for imatinib in CML and trastuzumab in the treatment of metastatic breast cancer. The reason for this is that the clinical trials are frequently reported with relatively short follow-up times, indicating that the effect is underestimated in the proportion of patients with good or very good clinical benefit, who survive longer than expected.

It is also important stop paying for the use of drugs if there is no evidence that they create value. It is thus necessary to follow up and verify early predictions. One way to generate the information needed at a reasonable cost is to introduce specific payment models for a limited introduction period. Payment during the introduction period can be seen as an investment in the development of information leading to better and safer decisions. This type of solution has been named "coverage by evidence development". Sometimes it is also called a risk-sharing agreement, because in some cases

ATC-kod4|(Alla)|Molecule|(Alla)|

SLL02_130109_Sales1998-2012_L01_L02AB_L04TalidOchLenali

SEK per Population (100 000)

35 000 000

30 000 000

25 000 000

20 000 000

15 000 000

Sjukvardsregion -Sverige

10 000 000

5 000 000

0 -I-,-,-,-,-,-,-,-,-,-,-,-,-,-

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Fig. 1. Sales of cancer drugs in Sweden Source: Pharmacy Statistics, http://www.ehalsomyndigheten.se/lakemedelsstatistik/.

the payment during the follow-up period is linked to a defined outcome, which is defined in the reimbursement decision.

This review of the introduction of cancer drugs in Sweden starts with a presentation of data on costs, including regional variations, and in the following section we compare the use of cancer drugs in Sweden with that in other countries. Such descriptive data comprise important background information for policy, but will not in themselves provide any evidence on efficiency and equity in the use of cancer drugs. This requires an analysis of value, and in the subsequent section we use tamoxifen, imatinib and trastuzumab to illustrate the issues involved in assessing the value of a cancer drug over its life cycle. This is followed by a review of how some cancer drugs have been introduced on the Swedish market, focusing on variations in use between the six health-care regions; each responsible for cancer care for a defined population. The observed differences in use have been discussed intensively, both from a patient perspective of equal access to new treatments, and from a cost and cost-effectiveness perspective. Are the observed differences evidence-based and in line with the stated objective in the Swedish health-care law that resources should also be allocated according to their cost-effectiveness?

In the final section of the paper we set out some principles we believe must be observed in developing policies for optimal use of medicines for cancer care - taking into account demands of patients for equal access and the principle of the cost-effective use of health care resources - and how these principles should be applied in the Swedish context.

Sales of cancer drugs in Sweden

Sales of cancer drugs in Sweden have risen sharply over the past decade. As shown in Fig. 1, the growth in sales has stagnated in recent years, which was predicted in the forecast we made a few years ago [4]. There are several explanations for this development. Some very important new drugs introduced 10-15 years ago (for example, rituximab, trastuzumab, imatinib and bortezomib) have, after a period of strong sales growth, reached a situation where most patients now receive them in treatment. Only a few drugs of similar medical importance have been introduced during the last decade. Several new drugs have been added in areas where there is competition, and the new drugs supplement and partially replace the ones already on the market. Impact on sales is thus limited. The costs of cancer drugs have also been reduced due to

1998-2011. SEK per 100,000 inhabitants.

patent expirations, and the price reductions have been greater than expected. Docetaxel and the so-called aromatase inhibitors (anas-trozole, letrozole and exmestane) are examples in which prices have fallen by over 90%. The high prices of several new cancer drugs - up to 100,000 Euros per treated patient and year - combined with limited survival gains have also delayed uptake and limited sales.

It should be kept in mind that the slowdown in sales growth in recent years does not apply only to cancer drugs, but is observed also for the pharmaceutical market as a whole.

All health-care regions (HCRs) have experienced large increases in the costs of cancer drugs in the last 10 years (Fig. 2). However, there is considerable variation between health regions in the use of cancer drugs, especially during the last 5 years. These regional variations are well known among leading oncologists, but they have not brought about any major debate. The explanation may be that the reasons for these regional variations and their consequences have not been analysed in detail. There is no individual-level data that would make it possible to study the causes of the difference in total costs: for example indications or treatment patterns. It is also impossible to determine whether the observed differences have any effect on treatment outcome. Both over- and under-use may occur, and the aggregate cost figures do not give any indication of which one dominates. A more detailed analysis of the relationship between costs and effectiveness is required to be able to make policy-relevant conclusions.

There are also significant variations in the use of individual cancer drugs. For example, the use of bevacizumab varies by a factor of four between the highest and lowest use in different HCRs. To relate these differences solely to demographic or related factors do not make sense. The most likely reason for the differences in how bevacizumab is used is the existence of local therapy traditions in different regions - what an economist would call "supply side factors". These differences in usage are notable given that there is no documentation supporting the cost-effectiveness of bevacizumab; most recently, the National Institute for Health and Clinical Excellence (NICE) in England found no support for the cost-effectiveness of its use in the treatment of ovarian cancer [5]. They came to the same conclusion as in previous evaluations of the use of beva-cizumab in colon cancer and breast cancer. The new guideline by the National Board for Health and Welfare in Sweden also gives low priority for the use of bevacizumab in the treatment of colorectal cancer, which is probably the indication with the most widespread use. It is reasonable to be generous in the early assessments of

Fig. 2. Population-based sales of all cancer drugs in Sweden's six health regions from 1998 to 2012. Use expressed in SEK per incident cancer case. Data for the western health-care region are incomplete for 2012 and therefore are not included. Parts of the reporting for Stockholm are missing, but only for some of the sales in November and December 2012, so the Stockholm data are included.

Source: Pharmacy Statistics, http://www.ehalsomyndigheten.se/lakemedelsstatistik/ and Swedish cancer registry, http://www.socialstyrelsen.se/register/halsodataregister/ cancerregistret/inenglish.

value, but many years after the introduction of a drug one would expect that its use, outside research projects, would be focused on indications where there is documented evidence for its cost-effectiveness.

A known pattern is that sales for a class of drugs over a certain period of time may increase significantly, and that the class of drugs dominates the sales. Such was the case with drugs for ulcers, hypertension and dyslipidemia in the 1980s and 1990s, and biologics for rheumatoid arthritis (RA) and multiple sclerosis (MS) during the 2000s. There are historically no cancer drugs among the biggest sellers, but in the last 10 years there have been some examples: e.g., rituximab, trastuzumab, imatinib and bortezomib. Trastuzumab and rituximab were numbers 7 and 8 on the list of the 15 best-selling drugs in Sweden in 2011. If we look at the sales for the entire period 2000-2011 in the large US market, there is no cancer drug on the list of the ten best-selling drugs.

On the Swedish market in 2011 there were just over 100 cancer drugs with total sales of 2800 million SEK. As shown in Table 1, the distribution of sales of drugs against cancer is very uneven. Of the 20 top-selling drugs, the five top sellers account for 54% of total sales. The 20 best-selling drugs account in turn for three quarters of total sales. Only a few drugs had sales of more than 100 million SEK in 2011. On the contrary, most cancer drugs have very modest sales, and about 80 drugs comprise a quarter of the sales. Among these are drugs that are widely used but cheap: e.g. tamoxifen (about 6 million SEK). There are also expensive drugs - such as lapatinib -which are (as yet) limited to use in a small number of patients (11 million SEK). Even with a focus on the newer cancer drugs there is no change in the overall picture.

The conclusion is that sales for most cancer drugs are modest, and a few products dominate. The top five cancer drugs accounted for 41% of total sales. This also includes all sales of rituximab, which is also used for the treatment of rheumatoid arthritis (RA).

More than 60 products have sales under 10 million SEK annually, and account for only 5% of the total sales of cancer drugs (see Appendix).

If we look at sales after the introduction year, products introduced over the last 5 years (2007-2011) account for 14% of total sales, or a total of 384 million SEK. Lenalidomide is the drug that has the highest sales, at 110 million SEK in 2011. Cancer drugs

introduced in the last 10 years (2002-2011) account for 36% of total sales. The best sellers are bevacizumab (introduced 2005) at 147 million and bortezomib (2004) at 120 million SEK.

Sales of products introduced before 1997 - i.e. those which currently only exceptionally have patent protection - account for 255 million SEK of the total sales. The best-sellers are paclitaxel (1993, 1992) with 50 million, leuprorelin (1987, 1984) with 145 million, doxorubicin (1978,1971) with 50 million and methotrexate (1950) to 59 million SEK (first year refers to the first sale in Sweden and the second to the first sale in the world). Note that methotrexate is also used in RA.

Sales of cancer drugs are thus dominated by a number of "bestsellers" in the same way as for the total pharmaceutical market. It is these bestsellers that account for the bulk of the sales, profits and revenue for financing research and development. These are also the drugs we focus on when calculating the value of new drugs. But it is important not to forget that drugs with small sales can still be very valuable for certain patient groups. There are also drugs that come late in the development in a specific therapeutic area and have small incremental benefits compared to those introduced previously and already established; such drugs therefore have low sales. It can still be profitable for a single company to launch them, but the importance for the patients overall is marginal, and it is seldom that late introductions lead to price competition.

Sweden in an international context

Having described the introduction of cancer drugs in Sweden, we will now describe how Sweden performs in an international comparison.

As shown in Fig. 3, Sweden is in an intermediate position in the use of new cancer drugs. France tops the use in Europe and is on a par with the US. The high usage in France is partly explained by the practice that most new cancer drugs are paid for separately, outside of regular hospital budgets. The comparison can also be affected by the system in France, with agreements on price and volume and the repayments from companies not reported in the statistics. Use of new cancer drugs in the UK is the lowest among the Western European countries and can be explained mainly by a conservative therapy tradition. In the Nordic countries, use in Sweden is now

Table 1

Twenty top-selling cancer drugs in Sweden 2009-2011.

Molecule/major indication Sales in million SEK Change Change % total sales of cancer

drugs in 2011

2009 2010 2011 2009-2010 2010-2011

Trastuzumab/breast cancer 289 304 326 5% 7% 11.8

Rituximaba/lymphoma 231 267 309 16% 16% 11.2

Imatinib/CML 204 213 208 5% -2% 7.8

Bevacizumab/CRC 107 130 147 21% 13% 5.3

Leuprorelin/prostate cancer 156 151 145 -3% -4% 5.2

Bortezomib/myeloma 81 96 129 18% 35% 4.7

Lenalidomide/myeloma 58 75 110 29% 46% 4.0

Pemetrexed/lung cancer 78 83 97 7% 16% 3.5

Sunitinib/RCC 55 61 65 11% 7% 2.3

Temozolomide/brain tumour 75 72 64 -3% -11% 2.3

Goserelin/prostate cancer 71 65 61 -8% -7% 2.2

Methotrexate/breast cancer 51 56 59 10% 5% 2.1

Erlotinib/lung cancer 47 50 51 6% 2% 1.8

Doxorubicin/lymphoma 46 53 50 15% -5% 1.8

Paclitaxel/ovarian cancer 46 46 50 1% 7% 1.8

Cetuximab/CRC 55 57 49 4% -14% 1.8

Capecitabin/CRC 44 46 47 6% 1% 1.7

Buserelin/prostate cancer 37 42 46 13% 8% 1.7

Docetaxel/breast cancer 181 169 43 -7% -75% 1.6

Dasatinib/CML 31 36 42 17% 15% 1.5

Source: Drug Statistics, Sweden.

CML, chronic myeloid leukaemia; CRC, colorectal cancer; RCC, renal-cell carcinoma. a It should be noted that the increase in use of rituximab to a large extent probably can be attributed to use in rheumatology.

|ATCgroup|L1 + L2A-B + Thalidomide + Lenalidomide|MoleculeTxt|(Alla)|

EUR per Population (100 000

6 000 000

5 000 000

4 000 000

France

S16 GloIntro 110211 AbsYear

Fig. 3. Sales of cancer drugs (registered before 1998 = mature and registered after 2002 = new) in selected European countries for the years 1999-2009. Euro per 10000 of population. ATCgroup L1 + L2A-B+Thalidomide + Lenalidomide. Source: IMS Health, http://www.imshealth.com/portal/site/imshealth.

3 000 000

2 000 000

1 000 000

lower than that in Denmark and at about the same level as that in Finland, but still higher than that in Norway.

Figs. 4 and 5 show an international comparison of the use of two important new drugs, trastuzumab and imatinib, measured in mg/case of breast cancer and leukaemia, respectively, in a selection of countries. This measure shows the proportion of patients who are treated, and eliminates the impact of potential differences in prices.

Most notable are the high sales in France. This is probably due mainly to trastuzumab, paid for separately outside the hospital's budget, but may also be because of increased volumes due to discounts as a result of agreements on price and volume. The use in Sweden and the UK is rather similar. The sales in eastern European

countries are much lower, and there are also large differences between these countries.

For imatinib, the differences between the European countries are smaller than for trastuzumab. The Swedish sales are slightly below average for the Western European countries. Remarkably, England and Sweden are relatively close to each other in the use of imatinib as well as trastuzumab. The use of cancer drugs in England is generally lower than that in Sweden. This could be interpreted by the fact that Sweden follows the NICE recommendations, at least for cancer drugs with proven cost-effectiveness.

A more comprehensive review of the introduction and use of new cancer drugs confirm the impression that Sweden does not stand out in an international comparison [6]. However, there are

|Dbeaae|Breaat|Mol8cule|Traatuzumab|

1999Q1 2000Q1 2001 Q1 2002 Q1 2003Q1 2004 Q1 2005Q1

S14ca_GloIntro_091001_AbsYearQiart |YearQuarter|

2006Q1 2007 Q1 2008 Q1 2009 Q1

Fig. 4. The use of trastuzumab (expressed in mg/case of breast cancer) in France, Poland, Russia, the UK, Sweden and Hungary 1999-2009. Source: IMS Health, http://www.imshealth.com/portal/site/imshealth and 1ARC, http://www.iarc.fr/.

Di8oa«e| Leukaemia Molecule In |Mg par Caae (year 2000^

2001 Q2 2002 Q2 2003 Q2

S15b_GloIntro_100615_AllCointries_AbsYearQiart

Country

Fig. 5. The use of imatinib (expressed as mg/case of leukaemia) in France, Poland, UK, Sweden, Czech Republic and Hungary, and the average in a section of the Western European countries (E13).

Source: IMS Health, http://www.imshealth.com/portal/site/imshealthand 1ARC, http://www.iarc.fr/.

50 000

40 000

30 000

20 000

10 000

2004 Q2

2005 Q2

2006 Q2

2007 Q2

2008 Q2

2009 Q2

no reliable international data from the last 5 years which, in light of the sharp decline in sales of cancer drugs in Sweden, might give a different picture.

The value of innovative cancer medicines

Decisions on the introduction and use of new cancer drugs should be based on knowledge (evidence) of their value. We have previously discussed the difficulties in making an assessment of value early in the development of a new cancer drug. In this section we describe in detail the methods and data used, based on a few examples.

The important principle is that the value is derived from the drug's overall effect on the patient. What we want to focus on is the necessity - and the difficulty in the early stages - of having evidence of these effects on the patient. How great is the increase in survival? How is the quality of life affected? How much does the treatment cost change? How is the possibility of working and performing other activities affected? Before we can have a meaningful

discussion on how these effects should be assessed, and how the appraisal of the different effects is made, we must know the magnitude of the different relevant effects observed.

Tamoxifen in breast cancer

In a calculation of the return on investment in health care in the United States for the period 1980-2000, breast cancer is identified as an area of high return; this is especially true of tamoxifen in early breast cancer to prevent recurrence of the disease [7]. The return is calculated as the number of QALYs (quality-adjusted life years) gained multiplied by a fixed price based on US studies of willingness to pay for a QALY. The high return from tamoxifen therapy for breast cancer is due to low cost combined with good effect. The patent for tamoxifen expired during this period, and controlled studies have confirmed the increase in survival from the treatment. It may be added that in the 1970s and early 1980s it was not proven that tamoxifen had an effect on survival, and the high cost of the drug was questioned. The pivotal study showing improved survival in

500 000

100 000 0--

1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 Ar

■^—Stockholm-Gotland Sverige

Fig. 6. The sales for tamoxifen in Sweden and Stockholm - Gotland region 1979-2004 per 100,000 population, current prices. Since 1980, consumer prices rose by about 300%. Source: Ref. [9, p. 10].

the adjuvant treatment was first published in 1988; 13 years after that tamoxifen first came onto the market. An important factor in this work was meta-analysis conducted by the EBCTCG (Early Breast Cancer Trialists' Collaborative Group) based on data from more than 200,000 women [8].

The social value of tamoxifen in Sweden for the period 1979-2004 was estimated at over 25 billion SEK ([9,10], p. 20). Much of the use and benefits came after the patent expired, and tamoxifen is still used - almost 40 years after its introduction - at a very low price (Fig. 6). The Swedish study confirms the results of the aforementioned US study, but also provides important additional information. First, that the gain in survival and quality-adjusted survival was three times higher in the adjuvant treatment than with disseminated disease. Second, it took a long time to arrive at the optimal duration of adjuvant treatment, depending on both the time it took to document the medical effects and that the price for the 5-year treatment was initially perceived as high. It is interesting that now, after so many years, there are discussions about 10 years of treatment, instead of 5, on the basis of new studies. There is also new evidence on the value of tamoxifen for primary prevention of breast cancer, which may provide even more value in the future [11,12].

Third, the example shows that it took a relatively long time after patent expiry before the price was reduced to the current level. Finally we note that, even taking inflation (changes in the consumer price index) into account, the price for tamoxifen, when it was introduced, was significantly lower than the prices for today's new cancer drugs.

Imatinibfor the treatment of chronic myeloid leukaemia (CML)/gastrointestinal stromal tumour (GIST)

Imatinib showed an overall survival benefit in CML in early clinical trials. As the follow-up period was limited, the estimated number of life years gained (LYGs) per patient was associated with great uncertainty. In a study of imatinib compared with interferon, estimated survival time was 15.3 and 9 years respectively, a survival gain of more than 6 years for those treated with imatinib [13]. The annual cost of treatment with imatinib is approximately 300,000 SEK, and for an individual patient treatment for many years amounts to several million SEK. The large survival benefit provides a reasonable cost-effectiveness, despite the high cost. Over time, the calculations have been revised and the results show that the survival benefits as well as the costs were underestimated in the early calculations. The number of LYGs is estimated at 10.0 and the number of QALYs gained at 8.9, resulting in a cost per QALY of around 350,000 SEK (50,000 USD), close to earlier estimates. Costs have

also increased compared to the previous calculations, as a result of longer treatment duration and higher price [14].

The research and development of imatinib is an interesting story in many respects, not least because it also illustrates some important moral and economic issues. The price of imatinib was 30,000 USD per year of treatment, and a programme was introduced to help patients who could not pay [15]. But over time, the price has increased, and the cost of treatment has increased to 90,000 USD [16]. The long survival time means that the costs of health care rise year by year as more and more patients receive treatment.

Two new drugs (dasatinib and nilotinib) that complement and substitute for imatinib were introduced in 2006 and 2007 respectively, which can further improve treatment outcome but at a higher cost. In 2012 the Food and Drug Administration (FDA) approved another three drugs for the treatment of CML: bosu-tinib, ponatinib and omacetaxine. The price for these is in the order of 100,000 USD per year. When the patent for imatinib expires in 2015 the price will drop significantly, while medicinal value for patients continues. But the economic issues will persist. The cost difference between different drugs for CML will be even more pronounced when the patent for imatinib expires. The new drugs provide opportunities to treat patients who no longer respond to previous treatments, and also provide opportunities to eventually find the optimal treatment for each patient. However, many new studies are needed to come up with the necessary evidence, and the financial implications must be considered.

Imatinib was introduced for a new indication, GIST, which requires new calculations to relate costs to benefits in terms of LYGs and QALYs [17]. This once again shows that a drug does not have just a single value, and that new evidence must be developed for each indication.

While early estimates of the cost-effectiveness of imatinib gave very accurate predictions, the later developments - with further introductions of drugs for the same indication - show that follow-up studies are essential to validate previous assumptions and to adjust treatment as new alternatives are added.

Trastuzumab in the treatment of HER2-positive breast cancer

Trastuzumab was introduced in Sweden in 2000 for the treatment of metastatic breast cancer. In 2005, trastuzumab was sold for about 92 million SEK in Sweden, and in 2011 sales amounted to 326 million SEK. The increase in sales is due mainly to the data presented in 2005 when trastuzumab is used as adjuvant therapy for early disease.

Cost-effectiveness depends on how patients are identified for treatment, because the benefits of treatment depend on whether the patient's tumour demonstrates an increase in a specific cell receptor (HER2) or amplification of the gene for the receptor. The choice of testing strategy becomes an economic issue in itself. The two tests used to determine the HER2 status, IHC (immunohisto-chemistry) and FISH (fluorescence in situ hybridisation), cost about 2000 and 5000 SEK respectively. Since the cost of trastuzumab is approximately SEK 330,000 for a year of treatment, the possibility of identifying the 15-25% of patients who might benefit is important also for economic reasons. The ability to identify patients who may benefit from a treatment is always an asset, but how the test should be used in an optimal manner must be assessed case by case and depends, among other things, on the cost of the test and the proportion of patients expected to have disease. The choice of testing strategy becomes part of the larger issue: how to optimise the treatment regarding cost and efficacy [18]?

In a Swedish study, the cost-effectiveness of trastuzumab in the treatment of metastatic breast cancer was estimated at 485,000 SEK per QALY gained using a FISH-based test strategy. It is a relatively high ratio, but it is within what would normally be considered

Fig. 7. Population-based sales of trastuzumab in the six health-care regions in Sweden 2000-2011. Use expressed in SEK per incident cancer case. Source: Pharmacy Statistics, http://www.ehalsomyndigheten.se/lakemedelsstatistik/ and Swedish cancer registry, http://www.socialstyrelsen.se/register/halsodataregister/ cancerregistret/inenglish.

a cost-effective treatment [19,20]. Cost-effectiveness of adjuvant trastuzumab for Sweden is estimated at 335,000 SEK (36,000 USD) per QALY gained. Cost-effectiveness is therefore better for the adjuvant treatment than for treatment of metastatic disease. This is not uncommon, and results of analysis of price in relation to the benefit in the treatment of metastatic disease (485,000 SEK) underestimates the benefits of potentially curative treatment [19,20].

A shift towards more "individualised treatment" will further increase the complexity of the evaluations because the number of treatment strategies will increase. Every indication must be studied separately for benefits and costs, as it involves additional treatment strategies. Treatment with trastuzumab in early breast cancer must be studied separately, but will also have an impact on the costs and benefits for the treatment of metastatic disease because many patients have already been treated once before. Adjuvant therapy also means that many more patients will be treated (1000 patients are considered for therapy, compared with 300 patients with metastatic disease), which increases the burden on the healthcare budget. It is therefore common that adjuvant treatment is subjected to more thorough economic analysis.

It is also important to ensure cost-effectiveness in the longer term. Trastuzumab, like tamoxifen, will probably be a valuable drug long after the patent has expired. If we assume that the price is halved after patent expiry, the cost/effectiveness ratio will be reduced by 50%. The net value to society of the drug is thus increased, while the value of the company that developed it decreases as sales are reduced.

The introduction of innovative cancer medicines in Sweden - some examples

Trastuzumab

The introduction of trastuzumab varied among HCRs in Sweden. This was probably related both to the high cost of the drug and to different interpretations of the clinical effectiveness oftrastuzumab in metastatic breast cancer. In 2005, data on a 1-year adjuvant use of trastuzumab was presented. The studies demonstrated an impressive reduction in disease relapse. This led to a rapid increase in the use of trastuzumab in all HCRs. This increase started already in 2005, i.e. before trastuzumab was approved for this indication

(April 2006). However, relatively large differences in use persisted. The introduction of trastuzumab in Sweden has been at a medium level, seen in relation to the rest of Western Europe. But the differences within Sweden are at least as big as the difference between Sweden and France (Fig. 7).

Imatinib

The introduction of imatinib was more uniform in Sweden, as was observed in the comparison between different EU countries. This was probably due to the relatively few patients (<100 new cases/year) being treated by a limited number of specialists, combined with generally accepted evidence on the effectiveness and cost-effectiveness of the drug (Fig. 8).

Drugs used in renal-cell carcinoma

Renal-cell carcinoma (RCC) accounts for about 2-3% of the cancer incidence in Sweden, and approximately 1100 patients are diagnosed per year. Because survival in metastatic disease is low, the prevalence remains low. RCC is the most deadly form of urological cancer, and the sixth leading cause of death from cancer in Sweden. Chemotherapy has had limited effect, and the only treatment - with a minor effect - has been cytokine-based immunotherapy with interferon or interleukin; the response rate is modest (about 15%) and toxicity is high. The introduction of the first new, targeted, tyrosine kinase inhibitors (TKIs) - sunitinib and sorafenib in 2006 - resulted in new treatment opportunities and the potential for improved outcome. Later several new targeted treatments have been approved in RCCs, such as the small molecules pazopanib and bevacizumab and the mTOR inhibitors temsirolimus and everolimus.

The approvals on drugs in RCC have been almost exclusively based on data related to progression-free survival, and only one study has shown an effect on overall survival.

In a recently published Swedish study, which looked for improvement in survival in patient registry data, the authors noted an increased survival in kidney cancer in Sweden, but it is difficult to tell how much of this improvement can be attributed to the introduction of new drugs in the area [21]. One possible explanation for the lack of a significant effect on survival may be that virtually

Fig. 8. Population-based sales of imatinib in the six health-care regions in Sweden 2011. Use expressed in SEK per incident cancer case. Source: Pharmacy Statistics, Cancer.

all drugs were approved on the basis of gains in progression-free survival. In order to study the long-term effect on survival from progress in treatment, one needs systematic data from patients with disseminated disease, something that is lacking today.

Thus, there are at present six new drugs used primarily in renal cancer (bevacizumab also has this indication, but has had limited uptake in RCC in Sweden). Several of these new drugs are also used for other indications such as liver cancer, neuroendocrine tumours, breast cancer and sarcoma. Kidney cancer is a research-intensive area, which is why some of the variation is probably due to many patients being in clinical trials and therefore receiving free drugs. The use of five RCC drugs is given in Fig. 9. Total sales for these five drugs amounted to about 130 million SEK in 2011.

are two drugs, cetuximab and panitumumab, approved for nonmutant KRAS patients.

All of these drugs will prolong progression-free survival in CRC, but have only modest effects on overall survival and in some special situations. None of the drugs have increased the survival in the adjuvant situation, and their impact on survival in the metastatic situation is limited. In the guidelines of the Swedish Board of Health and Welfare these antibodies are given low priority. The exception is the use of EGFR antibodies in potentially surgically treatable disease spread only to the liver or lung.

There are major variations in the use of bevacizumab in Sweden (Fig. 10). It is notable that in some regions (Stockholm and Southern) its use was significantly decreased in 2012. Data for Stockholm for November-December 2012 are incomplete.

Bevacizumab, cetuximab and panitumumab in the treatment of colorectal cancer

Until the late 1980s the general opinion was that medical treatment of colorectal cancer (CRC) had little or no effect. Improvements in survival data were due mainly to the development of diagnostic and surgical techniques. After the publication of data on adjuvant therapy with 5-fluorouracil (5-FU) in the 1980s and 1990s, CRC developed into an area where the use of drugs increased dramatically. In the 1990s it was shown that irinotecan and oxaliplatin, in addition to 5-FU, have an effect on CRC. These drugs are still the standard treatment for both early and advanced CRC. Adjuvant 5-FU (now also an oral treatment) in combination with oxaliplatin results in improved survival for stage III patients (spread to lymph nodes), while the value for stage II patients (tumour grows through the intestinal wall) is uncertain. For stage I patients (only local disease) surgery remains the standard treatment.

Biological treatment with bevacizumab (angiogenesis inhibitor) has been approved as first-line therapy for advanced CRC. Beva-cizumab now has a number of other indications (breast, lung and kidney cancers), but the breast cancer indication in particular has been discussed and the FDA in the USA has withdrawn its approval.

A recent development in CRC is the identification of a subgroup of patients with a particular non-mutated gene expression called wild-type KRAS (approximately 50%). Patients in this subgroup are the only ones who will benefit from a new class of drugs - the epidermal growth factor receptor (EGFR) inhibitors. At present there

Examples of drugs introduced 2011-2012

The Swedish Pharmaceutical and Dental Reimbursement Board (TLV), as well as the Swedish Association of Local Authorities and Regions (SKL), have intensified their role in the assessment of new cancer drugs during recent years.

Ipilimumab, a new drug and a new immunological treatment principle for the treatment of disseminated melanoma disease (Fig. 11), was approved in June 2011. Treatment with ipilimumab consists of four injections, and the list price is close to 800,000 SEK per treated patient. The SKL in collaboration with the Regional Cancer Centre (RCC) took on the role of negotiating at national level. It was not until the end of June 2012 that the SKL group for new drugs (NLT) reached an agreement on a national discount. From a patient perspective, obviously this delay of 1 year is not acceptable.

Vemurafenib, the other new drug for metastatic melanoma (Fig. 11), was approved at the end of 2011 by EMA (2011) and reached the market in March 2012. The cost of the drug is high - around 80,000 SEK/month - and survival impact is limited (3.9 months). The TLV's decision came in October 2012 and it found that the drug had a QALY cost that was above the TLV limit. Vemurafenib was introduced in the EU with a price 35-36% above the list price in the United States, which is surprising because prices in the EU tend to be lower than in the US. NLT has now come to a rebate agreement. The problem with a solution between SKL/NLT/RCC in collaboration and respective pharmaceutical companies is that some central

Fig. 9. The use of five kidney cancer drugs in the six health-care regions in Sweden 2011. Use expressed in SEK per incident cancer case. Source: Pharmacy Statistics, http://www.ehalsomyndigheten.se/lakemedelsstatistik/ and Swedish cancer registry, http://www.socialstyrelsen.se/register/halsodataregister/ cancerregistret/inenglish.

Fig. 10. The use of bevacizumab in the six health-care regions in Sweden 2005-2012. Use expressed in SEK per incident cancer case. Source: Pharmacy Statistics, http://www.ehalsomyndigheten.se/lakemedelsstatistik/ and Swedish cancer registry, http://www.socialstyrelsen.se/register/halsodataregister/ cancerregistret/inenglish.

budget funds are not linked to the introduction. Therefore the companies must, as before, proceed with negotiations at the local level.

In the prostate cancer field, two new drugs were introduced in 2011 (Fig. 12). First, abiraterone, a new hormonally active drug, was introduced for the treatment of patients with metastatic prostate cancer refractory to hormonal treatment; second, cabazitaxel, a new chemotherapy agent, was approved for the same patient population in early 2012. TLV evaluated abiraterone in June 2012 and found that the drug was not cost-effective. The TLV has also commented on cabazitaxel within the context of an ongoing clinical drug project and concluded that cabazitaxel was not cost-effective. The rejection of abiraterone by the TLV has been followed by negotiation between NLT and the company in December 2012. They reached an agreement, which provides a limited discount - however, in our opinion, far from the NICE level (see below).

It is interesting to compare the "undisclosed" discounts in Sweden on abiraterone, ipilimumab and vemurafenib with what NICE accomplished in England. Discount levels in England appear to

be far higher than those achieved in Sweden by the SKL/NLT/RCC in collaboration. One reason for this may of course be that the Swedish market is much smaller, and that a central agreement does not guarantee a regional/local use. One may also question whether the SKL has taken on a mandate that should reasonably be taken on by a governmental organisation (if one wants a national solution, within the national budget) or regional/local (where the budget is today). One should also expect similar discount terms for England (Table 2).

Discussion and conclusions

What is unique about cancer?

Cancer comprises many different diseases that represent very different challenges in terms of diagnosis, treatment and follow-up. Many drugs used in the treatment of cancers are approved with limited data on the impact on survival. This means that

Fig. 11. Use of new melanoma drugs in the six health-care regions in Sweden 2011-2012. Use expressed in SEK per melanoma mortality. Source: Pharmacy Statistics, http://www.ehalsomyndigheten.se/lakemedelsstatistik/. Cause of death registry, http://www.socialstyrelsen.se/english.

Fig. 12. The use of new prostate cancer drugs in the six health-care regions in Sweden 2011-2012. Use expressed in SEK per prostate cancer mortality. Source: Pharmacy Statistics, http://www.ehalsomyndigheten.se/lakemedelsstatistik/ and Cause of death registry, http://www.socialstyrelsen.se/english.

Table 2

Cost per quality-adjusted life year (QALY) estimates for selected newly introduced cancer drugs.

TLV (thousand SEK) NICE (thousand SEK)

Abiraterone - prostate cancer 1300 490a

Bevacizumab - ovarian cancer Not evaluated 1357-1707

Ipilimumab - malignant melanoma 1080 447a

Vemurafenib - malignant melanoma 1050 466-549a

Calculations from the National Institute for Health and Clinical Excellence (NICE) based on undisclosed discounts. Calculated on 1 GBP= 10.60 kronor. a In several cases.

post-approval follow-up and collection of "real-life" data are key in evaluating cancer drugs. In addition, cancer drugs are often used in combination or in sequence with each other, a practice which also needs to be evaluated in clinical practice. It is the total impact and cost of various treatment strategies that the health-care system needs information on to provide the best possible care.

A new aspect of cancer treatment is the high prices of several anticancer drugs introduced in the last decade. It commonly comes with a price tag of 60,000-70,000 SEK per treatment month, or

about 800,000 SEK per year. This high price can be explained partly by the high cost of developing new cancer drugs, but is nevertheless a problem for the health service and the community. The pharmaceutical cost of treating a patient may be equal to the cost of a doctor's salary for a year. This means that there is an alternative use of resources, within both cancer care and other areas of health care. Health care is therefore forced to strike a balance between how much should be spent on a new cancer drug in relation to other health-care interventions. These choices are not easy, but

unfortunately they are necessary. Because they are so important, they must be taken transparently and based on rational criteria, with the aim of creating the most efficient and equitable care possible.

The problem of prices is different from a societal perspective. The prices do not reflect the costs of producing and using the drugs. If one makes a comparison with the prices for going over the Ore-sund Bridge (the bridge between Sweden and Denmark), the cost of one passage has no relation to the cost of the passage itself. The bridge is there, and the additional cost of one or several thousands of vehicles passing will be just about the same. The prices for new cancer drugs represent mainly a reward for the investments the company have made in developing the drug, and a compensation for the costs of producing the substance. Similarly, financial charges for crossing the Oresund Bridge almost exclusively relates to the costs associated with building the bridge. When the patent on a drug expires, it is not uncommon for the price fall by over 90%. From a societal perspective, it is then optimal to treat all patients who might benefit from the drug, regardless of the price. For the pharmaceutical company it is not primarily the price but the total revenues that are vital to the profitability of developing new cancer drugs.

Sorafenib for the treatment of advanced renal-cell cancer may illustrate the problem. The cost of treatment with the drug approved in Sweden (is about 35,000 SEK per month). However, sorafenib is also available in a generic form, made in India, at a price of approximately SEK 1200 per month [22]. In order to create incentives for innovation, it is necessary to pay the company that developed the drug more than just manufacturing costs until the patent expires in 2020. The question to be answered is: how much? Still, at the same time it is important that payment is made in a way so as not to hinder those patients who might benefit from the drug from getting it. It would be of mutual interest to have an agreement between the company and the health-care provider giving higher total revenues, although the price per treated patient will be lower.

Another question is: how should the products ofthe same "class" be used and paid for? The principle today is that they are usually introduced at the same price as the first drugs in that class launched in the market. New products will lead to some increase in the overall market, but the main effect is that they share the market.

Different approaches to handling the high international prices of cancer drugs

International prices are determined by the ability and willingness to pay for cancer drugs by private insurers in the US. However, those prices are not directly relevant for Sweden, since the actual prices paid by private and public health insurers are lower because of rebates and co-payments. In the US it is also common for companies to pay at least part of the co-payments that patients have to pay to get access to the drug. These can be up to 20% of the price, which means up to 12,000-15,000 USD per year. Cancer is unfortunately a common cause of personal bankruptcy in the US [23].

Cancer drugs are also commonly discounted to hospitals and treating oncologists, which means that the price paid is lower and varies between different customers. The system in the US - where oncologists purchase and administer the drug, and are then reimbursed by the insurance company - has been questioned [24]. In an article in Health Affairs, the head of cancer care within the United Healthcare, Minnesota, argues for a compensation system based on performance [25].

It is thus not meaningful to compare drug prices in the US with drug prices in Sweden where, until recently, no discounts were given and there are no co-payments. The level of health-care expenditures - and salaries for oncologists and prices for other

health-care resources - are also much lower. It is therefore desirable to develop a new compensation system that encourages better use of medicines, leading to more cost-effective care.

England, like Sweden, has low or no co-payments for cancer drugs. But increasingly, new cancer drugs are introduced in the UK with a market access agreement, which in essence is a rebate on the price. The price adjustment is done by negotiations between the companies and NICE, which evaluates and advises on the use of such new cancer drugs. The basis for the agreements is an estimate of the drug's cost-effectiveness, expressed as cost per QALY gained. This ratio should not be higher than 20,000-30,000 GBP, or in exceptional cases 50,000 GBP per QALY. If the cost per QALY is higher, NICE usually recommends that the drug should not be used. This was the case in a recent evaluation of bevacizumab in the treatment of ovarian cancer [5]. Similarly, NICE first recommended against the use of abiraterone for the treatment of prostate cancer in the NHS, but the recommendation was later changed on the basis of an agreement reached on an undisclosed discount on the list price.

In the US, as well as in England, the final prices paid are not official, although it is possible to make an estimate of the size of the discount. Therefore, we see a movement where the price for new cancer drugs will be subject to national/local agreements, and that the previous model with a defined "global" price is about to be abandoned. The wide variations in income level between different countries make it difficult to maintain a uniform global price, supporting a development in this direction.

What can and should we do in Sweden?

The development of new cancer drugs is a process in which Sweden has little influence. The drugs come to market through approval by the European Medicines Agency and Sweden can only decide which patients they should be used and paid for. There are currently two separate ways for patients to get access to new cancer drugs in the Swedish public health-care system.

One route is through the decision by the TLV that they should be included in the benefit scheme for prescribed medicines. Cancer is a serious disease, and available treatments often have serious side effects and limited effectiveness. Access to new cancer medicines may be important, not to say vital, for the patients. The two overriding criteria for reimbursement are equal access to health care and that patients with the greatest need should have priority. According to these criteria, most cancer medicines will be reimbursed. The third criterion, cost-effectiveness, is more problematic. Only in cases where the new treatment has a similar or lower price than the existing medicines is it easy to decide that it should be included in the drug benefit scheme. However, in most cases the price and effectiveness are higher, and the cost of treatment must be weighed against the value of the treatment. A high price requires evidence for high value, which may be difficult to produce. The result, given the present situation in Sweden, is that new drugs are introduced slowly, to a small number of patients, and that not all patients who could benefit from a drug have access to it, at least initially.

The second way for patients to get access to cancer drugs is through the county councils that pay for cancer care, including drugs, at the hospitals. For drugs paid through hospital budgets there is no formal process for assessment of cost-effectiveness; which drugs to use is an administrative and clinical decision. In many counties, the oncology clinic is responsible for all medications used, including those that are prescribed and dispensed through pharmacies, so there is basically no difference between the two systems for cancer drugs from a payment and cost perspective. It is also up to the oncology clinics whether they want to use drugs that are recommended, or not recommended, by the TLV. There are a number of examples of companies choosing to make an agreement

with the county instead of going to the TLV for oral cancer drugs. County councils can also make non-public agreements with individual companies. The framework for these agreements is currently under discussion.

Having two different systems for making assessments and decisions about reimbursement and use of cancer drugs is not rational. In addition, both routes to public payment and use have pros and cons, which need to be taken into account when designing a more optimal system.

The TLV process includes only prescription drugs. Many cancer drugs are given as injections or infusions, and are therefore, at least at present, not assessed by the TLV (requisition drugs) even if they are used in ambulatory care. A second problem is that the TLV in principle grants subsidy for a particular product for a particular indication. Since value is dependent on the use, this changes with new indications. A third problem is that the price is official. This can affect the price the company can obtain in other countries, through the system of international reference pricing.

There are also problems with the "county process". First, it may lead to undesirable regional differences. However, there is no documentation to show that the observed differences in overall access to new cancer drugs lead to differences in health outcomes [26]. Another problem is that a decentralised solution would give small counties an unfavourable position in the negotiations. This problem is limited as cancer care is concentrated into six HCRs and can be overcome through cooperation between counties within an HCR. A third problem with a decentralised solution would be that financial aspects dominate decisions at local level. This is balanced by the obligation of the county councils who are responsible both for the costs and also for providing fair and effective care. The best solution is therefore that the county councils negotiate both price and quantity, instead of first determining the price at the central level and then quantities at the regional/local level.

Regional versus national roles and responsibilities

The basic characteristic of the Swedish health-care system is the responsibility of the county council for the population's health, and the authority of the county council to levy taxes to finance health care. This means that it is the county council's responsibility to make the trade-off between the objective of improved quality of care and the resources and taxes that it entails. It is also the county council that is responsible for allocation of resources within the health-care system.

This leads us to the conclusion that the regional model, with responsibility of county councils/regions, is the one which should be developed to adapt to the new developments in cancer care. The regional cancer centres (RCCs), which are developed with support from the government to coordinate cancer care at the regional level, also back this approach. However, it does require that the county councils/regions build information systems and skills for effective decision-making and governance. It is also important that the decision-making process will not be unnecessarily complicated, time-consuming and costly.

This does not exclude the presence of national interests for the improvement of cancer care. National interests are expressed in national legislation and the decisions of the national authorities. If we look specifically at cancer drugs, there are now a national cancer strategy and a national pharmaceutical strategy in place. There are also national guidelines for treatment of various diseases, including cancer, expressing demands for national standards. The guidelines for the major tumour groups developed by the National Board for Health and Welfare are also important to achieve good and cost-effective cancer care. For support of this approach, see the recent policy review by the National Audit Office [27].

The way forward

This review of cancer drug introductions in Sweden reveals a need to improve the process. A key factor is to define the roles of national and regional decision-making to make sure that they are coordinated and support each other. A process is needed for a national assessment of the cost-effectiveness of cancer drugs, as with all new medical technologies. Cost-effectiveness is an important criterion for the allocation of health-care resources. Swedish health-care law also stipulates that this principle should be followed. Therefore, there is a national interest in assessing cost-effectiveness and in following up that the decisions made at the county level are in line with the law. TLV has extensive experience in making assessments for prescription drugs and from a pilot project for requisition drugs. It would be a natural extension to give the TLV this responsibility for all (cancer) drugs. We see several advantages to this. The first is that the responsibility rests with an agency that is guided by legislation. Second, the TLV has developed collaborations with Lakemedelsverket, the Swedish Medical Products Agency, SBU the Swedish Council on Health Technology Assessment, and the National Board of Health and Welfare responsible for national clinical guidelines. There is rationality in cooperation and division of tasks by government agencies with responsibilities in the same field. The opportunities for engaging the county councils in assessment of new drugs should be explored.

One problem with the current mandate for the TLV is that decisions on reimbursement are linked to a certain price. This link to price control should be removed and replaced with free pricing. The TLVs assessment and recommendations could instead, like the recommendations by NICE, be based on a defined price. The recommendation could then be used by the county councils for contracting for prescription drugs, in the same way as can be done today for hospital drugs, including requisition drugs used for ambulatory treatment. All cancer drugs should be handled in the same way, regardless of whether they are consumed at home or at the hospital clinic. The system in Canada for assessment of cancer drugs, with a central review as a guide for decisions at the provincial level is an example of how this can work (www.pCODR.ca).

There is no need for a central authority to negotiate prices for new cancer drugs. Payments based on value should be the guiding principle at the regional level. Since it is difficult to determine the value and use before the drug is studied in clinical practice, it is also impossible to determine a price up front. On the basis of the health economic evaluation, one can evaluate the cost-effectiveness based on different indications/assumptions. It will be up to the county to use this information when negotiating with companies and making agreements about use, where price is one parameter.

If the price is determined at the central level, it must be linked to the expected use - i.e. volume - for it to be meaningful. But the TLV has no control of volumes for drugs that are either included or excluded from the reimbursement scheme. As mentioned earlier, there is a risk that the central price is set based on the most valuable indication. That will prevent use in other patient populations until the patent expires. This could be avoided if pricing was constructed as a two-part tariff, where those additional patients can be treated at a heavily discounted price. It would encourage the use within indications for which the value is lower or unclear. Such a two-step tariff is common in the pricing of goods and services with high fixed costs and low marginal costs, and has been proposed for the pharmaceutical sector in a paper by Person et al. [28]. It also links to discussions on "patent acquisition" as a model for achieving both dynamic and static efficiency [29]. Practical examples are few because of the difficulties of organising "buyers" and dividing the costs between them [30]. The French model, with price-volume agreements at the central level are combined with "free access" to

the drug within the health-care system can be seen as an approximation of this approach.

Central pricing requires a national budget for innovative drugs, and could be an option for an introductory period of 3-5 years. Those drugs would thus be paid outside the normal county council budgets. But such a system needs to be carefully managed in order to provide the correct incentives for use of innovative drugs. A system with regional responsibility for payments of innovative cancer drugs, as is the case for all other resources needed for cancer care, is most consistent with the regionalised health-care model in Sweden.

Introduction and monitoring of new cancer drugs at the regional level

The responsibility for using and monitoring the new cancer drugs should, in our view, be on the county council/regional level, because it gives the best opportunity to assess the benefits for patients and balance them against costs. The best opportunity to make an assessment of the costs and benefits of a drug's use for various indications is also at the regional level. The county council and the managers and doctors who are responsible for cancer care must also be the ones responsible for collecting relevant data for monitoring clinical effectiveness. It is also on the regional level where we find the best skills to enter into agreements with pharmaceutical companies. These agreements should be linked to treatment outcome. There are many advantages to this - also for the pharmaceutical industry. To be competitive, it is important to know what the health-care system demands and is willing to pay for. Close contacts with providers and payers give information and incentives to develop products and services that suit medical needs.

The two main goals of equal access to care and cost-effective use of health-care resources must be monitored at the national level. Data on use oftreatments must be recorded at the individual patient level and compiled so that it is possible to analyse outcome and

Table A1

Sales of cancer drugs in Sweden: 2011 sales after falling sales value.

Drug Sales (millions SEK) Per cent of total sales

Trastuzumab 326 11.8

Rituximab 309 11.1

Imatinib 208 7.5

Bevacizumab 147 5.3

Leuprorelin 145 5.2

Bortezomib 129 4.7

Lenalidomide 110 4.0

Pemetrexed 97 3.5

Sunitinib 65 2.4

Temozolomide 64 2.3

Goserelin 61 2.2

Methotrexate 59 2.1

Erlotinib 51 1.8

Doxorubicin 50 1.8

Paclitaxel 50 1.8

Cetuximab 49 1.8

Capecitabin 47 1.7

Buserelin 46 1.7

Docetaxel 43 1.6

Dasatinib 42 1.5

Letrozol 40 1.4

Anastrozol 33 1.2

Bicalutamide 33 1.2

Nilotinib 33 1.2

Azacitidin 30 1.1

Sorafenib 30 1.1

Talidomide 23 0.8

Everolimus 22 0.8

Gemcitabine 21 0.8

Yperite analougues 20 0.7

value. Regional differences will continue to be present, but this is not necessarily a problem if they are part of the search for optimal treatment strategies. What is not acceptable is if differences persist over time, without any explanation. Variations in treatment practices and patient outcomes should be published and debated. This will lead to improvements and differences will probably decrease.

For regions/county councils responsible for the introduction of new cancer drugs it is important to balance investments in innovative drugs against other interventions designed to improve care for cancer patients. New drugs may prolong survival and possibly cure some cancer patients. However, it is important that high-quality cancer care should provide all patients with good care in all stages of the disease. New drugs are a part of this process, but they must be seen in relation to the overall aim of the health service and bring added value to society at a reasonable cost.

Conflict of interest

None of the authors have any specific conflicts of interest related to this paper.

Acknowledgements

This is a revised version of a report prepared for the SNS, Centre of Policy Analysis, Stockholm, Sweden. We are grateful for comments on the revision by an unknown reviewer and to the SNS for supporting this study, as part of the SNS project "Value of pharmaceutical innovation" (http://www.sns.se/sites/ default/files/vardet_av Jakemedel_inlaga_web.pdf).

Appendix.

See Tables A1 andB1.

Cumulative sales (millions SEK) Per cent cumulative sales

326 11.8

635 22.9

843 30.4

990 35.7

1135 41.0

1264 45.6

1374 49.6

1471 53.1

1536 55.4

1600 57.8

1661 60.0

1720 62.1

1771 63.9

1821 65.7

1871 67.5

1920 69.3

1967 71.0

2013 72.6

2056 74.2

2097 75.7

2138 77.1

2171 78.4

2204 79.5

2237 80.7

2267 81.8

2298 82.9

2321 83.8

2343 84.5

2364 85.3

2384 86.0

Table A1 (Continued)

Drug Sales (millions SEK) Per cent oftotal sales Cumulative sales (millions SEK) Per cent cumulative sales

Epirubicin 20 0.7 2404 86.8

Oxaliplatin 20 0.7 2424 87.5

Panitumumab 18 0.7 2442 88.1

Gefitinib 17 0.6 2459 88.7

Carboplatin 17 0.6 2476 89.4

Fulvestrant 16 0.6 2492 89.9

Vinorelbin 14 0.5 2506 90.4

Anagrelide 14 0.5 2520 90.9

Cabazitaxel 13 0.5 2533 91.4

Exemestane 13 0.5 2546 91.9

Abiraterone 13 0.5 2559 92.3

Irinotecan 13 0.5 2572 92.8

Pazopanib 12 0.4 2584 93.2

Trabectedin 12 0.4 2595 93.7

Lapatinib 11 0.4 2607 94.1

Methylaminolevulinate 11 0.4 2617 94.5

Cytarabine 9 0.3 2627 94.8

Other chemotherapy drugs 9 0.3 2635 95.1

Alemtuzumab 8 0.3 2644 95.4

Topotecan 8 0.3 2652 95.7

Etoposide 8 0.3 2660 96.0

Fluorouracil 8 0.3 2668 96.3

Fludarabine 7 0.3 2675 96.5

Cyclophosphamide 7 0.2 2682 96.8

Triptorelin 6 0.2 2688 97.0

Tamoxifen 6 0.2 2694 97.2

Hydroxycarbamide 6 0.2 2700 97.4

Ifosfamide 5 0.2 2704 97.6

Ipilimumab 4 0.2 2709 97.8

Eribulin 4 0.2 2713 97.9

Amsakrin 4 0.1 2716 98.0

Streptozotocin 3 0.1 2720 98.2

Vincristine 3 0.1 2723 98.3

Temsirolimus 3 0.1 2726 98.4

Mercaptopurine 3 0.1 2729 98.5

Clofarabine 3 0.1 2732 98.6

Estradiol 3 0.1 2735 98.7

Vinflunine 3 0.1 2738 98.8

Mitomycin 3 0.1 2740 98.9

Ofatumumab 2 0.1 2743 99.0

Cisplatin 2 0.1 2745 99.1

Asparaginase 2 0.1 2747 99.1

Daunorubicin 2 0.1 2749 99.2

Mitotan 2 0.1 2751 99.3

Mitoxantron 2 0.1 2752 99.3

Aminolevuline acid 2 0.1 2754 99.4

Cladribine 1 0.0 2755 99.4

Idarubicin 1 0.0 2757 99.5

Bleomycin 1 0.0 2758 99.5

Melphalan 1 0.0 2759 99.6

Medroxiprogesterone 1 0.0 2760 99.6

Flutamide 1 0.0 2761 99.7

Bexarotene 1 0.0 2763 99.7

Estramustine 1 0.0 2764 99.7

Procarbazine 1 0.0 2765 99.8

Dacarbazine 1 0.0 2766 99.8

Busulfan 1 0.0 2767 99.8

Trofosfamide 1 0.0 2767 99.9

Nelarabine 0 0.0 2768 99.9

Tretinoin 0 0.0 2768 99.9

Vinblastine 0 0.0 2768 99.9

Alkylating agents 0 0.0 2769 99.9

Lomustine 0 0.0 2769 99.9

Megestrol 0 0.0 2769 99.9

Clorambucil 0 0.0 2770 100.0

Tioguanine 0 0.0 2770 100.0

Vindesine 0 0.0 2770 100.0

Toremifene 0 0.0 2770 100.0

Degarelix 0 0.0 2771 100.0

Raltitrexed 0 0.0 2771 100.0

Catumaxomab 0 0.0 2771 100.0

Dactinomycin 0 0.0 2771 100.0

Other alkylating agents 0 0.0 2771 100.0

Other cytotoxic drugs 0 0.0 2771 100.0

Pegaspargase 0 0.0 2771 100.0

Teniposide 0 0.0 2771 100.0

Treosulfan 0 0.0 2771 100.0

Table B1

Sales of cancer drugs in Sweden (ATC kod 1 + 2A + 2B + thalidomide + lenalidomide) 2011 distributed after the year of introduction.

Drug Year of introduction (first sales) Sales (millions SEK) Cumulative Sales (millions SEK) Per c

Abiraterone 2011 13 13 0.5

Eribulin 2011 4 17 0.6

Ipilimumab 2011 4 21 0.8

Cabazitaxel 2011 13 35 1.2

Catumaxomab 2011 0 35 1.3

Degarelix 2010 0 35 1.3

Estradiol 2010 3 38 1.4

Ofatumumab 2010 2 40 1.4

Pazopanib 2010 12 52 1.9

Vinflunine 2010 3 55 2.0

Aminolevuline acid 2009 2 56 2.0

Azacitidine 2009 30 87 3.1

Nelarabine 2009 0 87 3.2

Temsirolimus 2009 3 90 3.3

Everolimus 2008 22 112 4.0

Lenalidomide 2008 110 221 8.0

Panitumumab 2008 18 240 8.7

Thalidomide 2008 23 263 9.5

Trabectedin 2008 12 275 9.9

Treosulfan 2008 0 275 9.9

Cytotoxic drugs 2007 0 275 9.9

Dasatinib 2007 42 316 11.4

Clofarabin 2007 3 319 11.5

Yperite analougues 2007 20 340 12.3

Lapatinib 2007 11 351 12.7

Nilotinib 2007 33 384 13.9

Pegaspargas 2007 0 384 13.9

Trofosamid 2007 1 384 13.9

Other Alkylating agents 2007 0 384 13.9

Raltitrexed 2006 0 384 13.9

Sorafenib 2006 30 415 15.0

Sunitinib 2006 65 480 17.3

Bevacizumab 2005 147 627 22.6

Bexaroten 2005 1 628 22.7

Erlotinib 2005 51 679 24.5

Gefitinib 2005 17 696 25.1

Other cytotoxic drugs 2005 9 705 25.4

Bortezomib 2004 129 834 30.1

Cetuximab 2004 49 884 31.9

Fulvestrant 2004 16 900 32.5

Pemetrexed 2004 97 997 36.0

Alemtuzumab 2001 8 1006 36.3

Alkylating agents 2001 0 1006 36.3

Anagrelide 2001 14 1020 36.8

Capecitabine 2001 47 1067 38.5

Imatinib 2001 208 1274 46.0

Methylaminolevulinate 2001 11 1285 46.4

Mitotane 2001 2 1287 46.4

Streptozotocin 2001 3 1290 46.6

Exemestane 2000 13 1303 47.0

Trastuzumab 2000 326 1629 58.8

Hydroxycarbamide 1999 6 1635 59.0

Oxaliplatin 1999 20 1654 59.7

Temozolomide 1999 64 1719 62.0

Irinotekan 1998 13 1732 62.5

Rituximab 1998 309 2040 73.6

Letrozole 1997 40 2080 75.1

Topotecan 1997 8 2089 75.4

Anastrozole 1996 33 2122 76.6

Bikalutamide 1996 33 2155 77.8

Docetaxel 1996 43 2198 79.3

Vinorelbin 1996 14 2212 79.8

Asparaginase 1995 2 2214 79.9

Fludarabine 1995 7 2221 80.2

Gemcitabine 1995 21 2242 80.9

Kladribine 1994 1 2244 81.0

Toremifene 1994 0 2244 81.0

Tretinoin 1994 0 2244 81.0

Flutamide 1993 1 2246 81.0

Paclitaxel 1993 50 2295 82.8

Idarubicin 1991 1 2297 82.9

Ifosfamide 1990 5 2301 83.0

Triptorelin 1990 6 2307 83.3

Buserelin 1988 46 2353 84.9

Epirubicin 1988 20 2373 85.6

Percent cumulative sales

Table B1 (Continued) B IJönsson, N. Wilking / Journal of Cancer Policy 2 (2014) 45-62 61

Drug Year of introduction (first sales) Sales (millions SEK) Cumulative Sales (millions SEK) Per cent cumulative sales

Goserelin 1988 61 2434 87.8

Carboplatin 1987 17 2451 88.4

Leuprorelin 1987 145 2596 93.7

Mitoxantrone 1987 2 2597 93.7

Vindesine 1985 0 2598 93.7

Amsakrin 1983 4 2601 93.9

Mitomycin 1983 3 2604 94.0

Etoposide 1982 8 2612 94.3

Tioguanine 1981 0 2612 94.3

Cisplatin 1980 2 2614 94.4

Dacarbazine 1980 1 2615 94.4

Megestrol 1979 0 2616 94.4

Teniposide 1979 0 2616 94.4

Doxorubicin 1978 50 2666 96.2

Lomustine 1978 0 2666 96.2

Bleomycin 1977 1 2668 96.3

Busulfan 1977 1 2668 96.3

Cyclophosphamide 1977 7 2675 96.6

Cytarabine 1977 9 2685 96.9

Dactinomycin 1977 0 2685 96.9

Daunorubicin 1977 2 2687 97.0

Estramustine 1977 1 2688 97.0

Fluorouracil 1977 8 2696 97.3

Clorambucil 1977 0 2696 97.3

Medroxiprogesterone 1977 1 2697 97.3

Melfalan 1977 1 2698 97.4

Mercaptopurine 1977 3 2701 97.5

Methotrexate 1977 59 2760 99.6

Procarbazine 1977 1 2761 99.6

Tamoxifen 1977 6 2767 99.9

Vinblastine 1977 0 2767 99.9

Vincristine 1977 3 2771 100.0

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