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2015-11-17 | 来源:51Due教员组 | 类别:更多范文

欧洲疾病负担评估
 
癌症是增加世界死亡率的主要原因之一,使全球负担持续快速增长。这标志癌症成为全球许多国家包括欧洲国家的主要问题,并表示在分配必要的财政资源,提供癌症治疗和护理癌症患者,同时保持获得健康权益之间取得平衡的卫生保健系统是一个很大的挑战和公共资源的有效配置管理。这成为在目前的经济环境下,当政府正在努力削减公共开支,以防止本国经济的进一步下滑特别重要的一个因素。值得强调的是,平衡创新抗癌药物的成本,收益和可用性不应损害需要它们的患者公平地获得这些药物的权利。 
 
区分癌症与其他疾病的特点是,癌症的医疗管理和相关的健康技术,包括药品,发展见证了近几十年来前所未有的加速,这通常被视为一种现代病。随着新抗癌药物的出现,患者的生存机会比以往任何时候都高。 
 
Assessing the burden of disease in Europe
 
Introduction
 
Cancer is one of the major causes of mortality in the world, and its global burden continues to increase rapidly. This flags cancer as a major problem for many countries worldwide, including European countries, and represents a great challenge for health care systems in allocating the necessary financial resources to provide cancer treatment and care to cancer sufferers while maintaining a balance between equity of access to health care and the efficient allocation and management of public resources. This became particularly important under the current economic climate, when governments are struggling to reduce public expenditure to prevent further downturn of their countries’ economies. Never-the-less, balancing the costs, benefits, and availability of innovative cancer drugs should not compromise the equitable access to these drugs by patients who need them.
 
One of the characteristics that distinguish cancer from other diseases is that the development of cancer’s medical management and related health technologies, including drugs, had witnessed an unprecedented acceleration in recent decades in response to what is commonly seen as a modern disease. With the emergence of new cancer drugs, patient chances of survival are higher than ever. With these novel agents entering the market as new entities with more tumor site specificity and efficacy, higher prices are to be expected. Unfortunately, publicly funded healthcare systems can not afford to fund all of these new and expensive drugs, leading to the creation of policies and methods to control the pricing and market access of these drugs. Yet despite their best efforts, equity of access to new and innovative cancer drugs could not be achieved for cancer patients in Europe (Wilking and J?nsson 2005)
 
European countries have different policies for the pricing and reimbursement of pharmaceuticals, including cancer drugs.
 
The World Health Organization is putting more focus on non-communicable diseases, including cancer.
 
Burden of disease in Europe
 
Although cancer can be traced to ancient times (WHO 2008), it was only during the later part of the twentieth century that the incidence of cancer increased significantly, partly because of the rise in life expectancy in large segments of the population, especially in Europe (Bray 2008), and partly because of the increased reporting of the disease as a result of the introduction of cancer screening programs and advancements in diagnostic technologies. Since cancer is a disease of old age, the increasingly aging population in Europe comprises a significant impact on cancer risk. This effect is accounted for in the International Association for Research on Cancer report (Ferley 2010 b) by directly standardizing cancer incidence rates according to global population age to produce Age-Standardized Rates (ASR) expressed as number of new cases per 100,000.
 
The global burden has more than doubled during the past 30 years and it continues to increase. In 2008, it was estimated that 25 million patients were living with cancer, 12 million were diagnosed with new cases of cancer and 7 million had died from cancer worldwide. This number is estimated to increase by 2030 to 75 million patients living with cancer (within five years of diagnosis), 27 million with new cases of cancer and 17 million deaths from cancer worldwide (WHO 2008).
 
In Europe, cancer incidence rates follow the global trend. In 2008, nearly 2.5 million individuals were diagnosed with cancer and around 1.3 million died from cancer in the European Union (EU 27) (IARC 2008). The incidence rate of different types of cancer in Europe is also rapidly increasing. The World Cancer Report (WHO 2008) estimates that there will be 4.1 million new cases of cancer, and 2.6 million deaths from cancer in Europe by the year 2030. This demonstrates that cancer has a heavy burden in Europe, and despite advances in cancer treatments, this rate continues to rise, which can be mainly attributed to population growth and ageing (Albreht et al 2008).
 
Cancer incidence rates in Europe vary between sexes, cancer types, and countries. Men in Northern and Western Europe had an ASRs of 303.5 and 337.4 respectively in 2008, which was attributed to high incidence of prostate cancer in the region. On the other hand, Women in Northern and Western Europe had an ASR of 249.4 and 250.9 respectively, mainly due to high rates of breast cancer (Ferly 2010 b). The International Association for Research in Cancer (Ferlay 2010 b) published cancer incidence rates according to type throughout Europe (EU27). The most dominant cancer types were Female breast cancer, prostate cancer, colorectal cancer and lung cancer respectively. Combined, they accounted for 53% of the total cancer incidence in 2008 per number of cases reported. Female breast cancer was the most frequently diagnosed type in Europe, With an estimated 338600 new cases (ASR 77.1), followed by 338600 new cases (ASR 72.4) estimated for prostate cancer, and 333330 new cases (ASR 31.6) of colorectal cancer, with Lung cancer ranking fourth in Europe, with an estimated 288100 new cases (ASR 30.1).
 
Mortality is another important measure as it gives a crude indicator of how significant the risk of disease is on the population, and the effectiveness of the health care system in addressing a certain disease like cancer. In Europe, Cancer mortality accounted for nearly 205 of all deaths. It was second most common cause of death after cardiovascular disease overall, and the main cause of premature death in people younger than 65 years of age in 28 European countries (WHO ROE 2010).
 
Differences between European countries can also demonstrate interesting observations. As shown in figure 1 below, Denmark, Ireland and Belgium have the highest ASRs in Europe, yet maintain a low to average mortality rate in comparison to other European countries. On the other hand, Hungary falls in the middle with regards to cancer incidence, but its cancer mortality rate is significantly higher than any other European countries. There are different factors that could explain this observation, mainly attributed to environmental factors, such as diet, social behavior and cultural practices (Bray 2008). The WHO – Regional Office for Europe (2010) estimates that 40% of the cancer burden is caused by tobacco use and excessive alcohol consumption. This variation in Europe can also be related to healthcare system performance in terms of the availability of cancer prevention programmes, screening programmes, control plans, accessibility to healthcare facilities and technological infrastructure (Alexe et al., 2008). But there are other factors that affect cancer burden such as the uptake of cancer drugs in the market as this paper demonstrates.
 
The Economic Burden of Cancer in Europe
 
Cancer can have a great economic impact on the health system as a result of direct costs of cancer treatment, and an even greater impact on society due to loss of income and the inability of patients to work, in addition to the possibility of death before the age of retirement (Wilking and J?nsson, 2005). With increasing incidence of cancer worldwide, the financial burden on healthcare system is greater than ever. For the purpose of this study, only costs related to pharmaceuticals in cancer will be taken into consideration.
 
The difficulty in managing cancer in any population lies in its complex nature, since it is not a single disease, there are many types of malignant tumors and each type requires complex health care interventions, including surgery, chemotherapy, radiotherapy and palliative care. Added to this, the cost of specialist healthcare professionals, expensive equipments, and sophisticated diagnostic procedures all add up to the heavy financial burden on the payer, be it the government, social insurance fund or patients themselves. Fortunately for patients in Europe, governments adopt the European social model which is based on common values including equality and social security (Liikanen, 2007, European Trade Union Confederation, 2007). This model drives public health systems to make cancer treatments available to cancer patients, especially complex and expensive ones that many people can not afford, transferring even more financial burden onto healthcare systems, which -in turn- pursue measures to reduce the financial burden on their resources and increase efficiency of the system such as health technology assessment and more strict pricing and reimbursement policies for pharmaceuticals.

Wilking et al (2009) estimated that the direct cost of cancer per capita in Europe was €148 (expressed in PPS [1] ), and the average percentage of expenditure on cancer from total healthcare expenditure was 6.3% in 2007 with the highest expenditure on cancer in Luxembourg, Norway and Switzerland, respectively. These three countries were also the top three ranking countries in general healthcare expenditure in Europe in 2008 as reported by the Organization for Economic Co-operation and Development (OECD, 2008) (Figure 2), emphasizing the correlation between general healthcare expenditure and expenditure on cancer care. Another interesting observation is the rapid increase in cancer costs. Wilking and J?nsson (2005) estimated that the average direct cost for cancer per capita in Europe was €120 PPS in 2002/2003, demonstrating that expenditure on cancer is increasing rapidly.
 
The level of expenditure on cancer drugs specifically, however, is rather difficult to define. Reports of different estimations of cancer drug costs vary significantly as they have different definitions of what a cancer drug is, they may include cancer drugs that are also used for other indications than cancer, drug prices reported may include wholesaler or pharmacy markups, and may include value-added taxes (Wilking and J?nsson, 2005). in addition, there are variations in healthcare and reimbursement systems, some countries provide cancer drugs in the ambulatory setting, where community pharmacies supply these drugs, adding markups and wholesaler fees to the ex-factory price of a drug. Other countries supply cancer drugs mostly through hospital pharmacies, where reimbursement of drug costs is different from the ambulatory sector costs. Regardless of this, the cost of cancer drugs takes a small share of the total drug cost; Wilking and J?nsson (2005) estimated the share of cancer drug cost to be 3.5% of the total drug cost in Europe in 2002-2003, but the issue that raises concerns in their study is that expenditure on cancer drugs in 25 European countries had risen from €5 billion in 1995 to €23 billion in 2005.
 
This alarming increase could be partially attributed to the increased incidence of cancer, and the transformation of cancer into a chronic disease as people live longer with cancer. But it is mainly because of the emergence of new and innovative cancer drugs, and because of the addition of new indications to already authorized cancer drugs (Wilking et al., 2009). On the other hand, it is important to both governments and the public, from an economic and a societal perspective, to develop new treatments for cancer and make them available to those who need them, when they need them. From this discussion, it is now prudent to discuss the importance of the recent advances in cancer pharmacotherapy, and how policies can protect and encourage pharmaceutical innovation while maintaining equity of patients’ access to the latest innovative drugs.
 
Advances in Cancer Pharmacotherapy
 
When cancer drugs were first introduced in the middle of the twentieth century, their mechanism of action relied on interfering with the cancerous cell division cycle and eventually killing the cell and the tumor. The only level of specificity of these drugs to cancer cells stemmed from the fact that cancer cells divide at a much higher rate, so cancer drugs would have a more substantial effect on cancer cells than on normal cells during the period they are inside the body. Yet, normal cells would still be affected by the toxic drug molecules, resulting in adverse effects that can be severe in many cases, and this toxicity could result in reducing the drug dose to a less than optimal one, or stop the treatment all together if the patient can not tolerate the drug.
 
It was because of this toxicity that the focus had shifted to developing more tumor-specific drugs. Aided by advancements in basic understanding of the pathophysiology of cancer, and in molecular and drug discovery technologies, tumor-targeting drugs were developed to specifically have their pharmacological effect on tumor cells, sparing normal cells from possible adverse effects. As a result, these drugs are potentially more effective and safer than conventional cancer drugs, and are seen as the preferable choice of treatment – if indicated - and the future of cancer therapy. Furthermore, many of these drugs represent a leap in treating certain cancers that did not have an established benchmark drug for treatment, casting light on these drugs as “breakthrough drugs”, such as the example of Sunitinib (Sutent?) indicated for the treatment of advanced/metastatic renal cell carcinoma, which –before the market entry of Sunitinib- was a very resistant type of cancer to chemotherapy (NICE, 2009). Having entered the market with a novel mechanism of action, and solid clinical evidence of it’s superiority to alternative treatments available in practice, Sunitinib simply demonstrated how important it is to adopt new and innovative medicines to governmental institution such as the UK National Institute of Clinical and Health Excellence which recommended the use of the drug in the UK despite its massive cost. Another advantage of targeted therapies is that it is becoming increasingly possible to determine whether an individual patient would respond to a certain targeted drug by measuring certain biomarker in the body, which avoids wastage of resources for those who would not respond, and better health outcomes for those who would (Zwierzina et al, 2007, McCabe et al, 2009).
 
On the other hand, some articles expressed doubts about the added value of tumor-targeting drugs over conventional drugs as clinical trials comparing these drugs to a standard comparator aim to prove that they are not inferior to the comparator rather than being superior (Grattini and Bertele’, 2002), and that simple preventative measures, such as smoking cessation, have reduced the burden of cancer far more than new cancer drugs have (Leaf, 2003). Added to that is the fact that many oncology clinical trials measure the outcome of drug treatment in progression-free survival rather than treatment of disease or alleviation of symptoms due to the nature of the disease, making the assessment of such added value highly subjective.
 
Like Sunitinib, all other new cancer drugs bare a hefty price tag as a result of increasingly high cost of development and marketing of these drugs. This increasing cost is due to the increasing complexity and cost of clinical trials in response to more stringent regulatory requirement from payers and regulators asking pharmaceutical companies to demonstrate the cost effectiveness of their new products, and due to the competition on recruiting the same clinical trial population in the developed world (Lewis, 2007). In addition, the manufacturing process of biologic cancer drugs (this study included 4 monoclonal antibodies centrally authorized since 2005) is more costly than conventional drugs since they are manufactured in a small number of extremely expensive bioincubators. McCabe et al (2009) illustrates how expensive the manufacturing process is:
 
“A bioincubator, which is typically dedicated to generating a single biologic, can cost >$1 billion, financed by venture capitalists expecting a 20% annual return on capital. Assuming that the manufacturing investment is made 2 years before licensing, a pharmaceutical firm would have to incur debt exceeding $1.4 billion for manufacturing alone before the product is launched.”
 
Consequently, new cancer drugs are some of the most expensive drugs in healthcare (Meropol and Schulman, 2007), and this is reflected in the current expenditure on cancer drugs. In a study that investigated the market uptake of targeted cancer drugs in eight European countries, it was found that expenditure on these drugs had increased by 40% between 1997 and 2007 (Obradovic et al, 2009). In light of this, payers and manufacturers have to work together to achieve a mutual level of agreement and a balance between encouragement of pharmaceutical innovation and healthcare cost containment. Yet drug costs vary between European countries, indicating the imbalance of power between governments and the industry, and how much weight is added to each side of the scale according to national priorities.
 
Pharmaceutical Innovation versus Cost Containment
 
As demonstrated above, new cancer drugs are arguably of great benefit to society, but are increasingly more expensive. On the other hand, demand is also increasing for these drugs, evident in the increase in the global sales, which are estimated to be growing by 12-15% annually, a significant increase over the 2007 rate of 6.4%, reaching $75-80 billion by 2012 (IMS Health 2008). Having seen the potential for huge profits, pharmaceutical companies invest billions of dollars on research and development of these innovative drugs, and with the continuous scientific breakthroughs in medicines and related technologies, more pharmaceutical and biotechnology companies are entering the oncology market with huge investments to an extent that makes this development pipeline one of the richest, reaching over 40% of pharmaceutical research and nearly 2000 molecules in research pipelines worldwide (Lewis 2007).
 
On the demand side, the increase of use of new cancer drugs by healthcare providers could be explained by the imbalance of national priorities as governments and social funds were putting more weight to the improvement of health outcomes (Lewis 2007), which targeted cancer drugs promise to improve, in addition to responding to pressures from patient groups and their physicians to adopt promising new cancer treatments, making access to these treatments a politically sensitive topic as demonstrated in the recent white paper by the UK Department of Health (2010), who will create a new £50 million Cancer Drug Fund in April 2011 to improve access to new cancer drugs for NHS patients while maintaining the promotion of pharmaceutical innovation.
 
As pharmaceutical companies are profit maximizers, they take advantage of the political sensitivity of cancer care to gain more market power for their products, and have more leverage in setting their pricing strategies. This is also aided by patent protection and complex/unique indications that grants a novel drug market differentiation. As a result of the expanding cancer budgets, national priorties have shifted towards the control of pharmaceutical expenditure (Mossialos and Oliver 2005). Payers began pursuing cost containment measures by reviewing their national drug policies, and in particular pricing and reimbursement policies, in addition to demand side measures that are outside the scope of this study. These new policies had a strong impact on the pharmaceutical market, making it more difficult for pharmaceutical business to maintain its viability and continue to produce innovative and profitable products.
 
The purpose of cost containment measures is to increase the allocative efficiency of a healthcare system from a policy maker point of view. These measures can be carried out to control price and/or volume of pharmaceutical products.
 
Yet patient around in Europe still do not have equitable access to these drugs (Wilking and Jnsson 2005)
 
From a policy perspective, cost containment regulations in Europe are currently part of a wider strategy aimed at making allocation more efficient, by reducing the economic resources absorbed by mature drugs on the one hand and rewarding investment in highly innovative medicines on the other. The pharmaceutical industry is facing substantial criticism from many directions (Barton and Emanuel 2005), being considered the main cause of the increasing expenditure despite the low numbers of new active ingredients with added therapeutic value recently launched Barton and Emanuel 2005, Joppi et al 2005, Apolone et al 2005. Big pharmaceutical companies argue that their research investments in Europe have been undermined by cost containment measures introduced by public authorities Vernon 2005, Danzon 2005. in Garattini et al 2007
 
Denmark
 
The healthcare system in Denmark is mostly a tax-funded public system, with most of the services provided free of charge for consumers. There are five regions in Denmark, the local authority in each region is responsible for funding and running hospital services, health insurance, general practitioners and other national health services.
 
The main body that regulates pharmaceuticals is the Danish Medicines Agency (DKMA), which deals with pharmaceutical product authorization, pricing, reimbursement, pharmaco-vigilance, pharmaceutical consumption and other statistics, in addition to promoting the rational use of drugs. The agency evaluates and authorizes new medicines according to their cost-effectiveness.
 
Prices of pharmaceuticals are not regulated by law; both pharmaceutical manufacturers and wholesalers are free to price their products as they wish, leaving market forces to control prices of medicines. Pharmaceutical manufacturers report their prices to the DKMA, and update them every two weeks. Wholesalers don’t have a standard profit margin as such, but margins are negotiated with pharmaceutical manufacturers on an individual basis. There are 14 hospital pharmacies in the whole of Denmark, who procure all hospital medicines from the Danish hospital purchasing agency (AMGROS), which is a purchasing partnership between the five Danish regions.
 
Regarding cancer drugs, they are mostly for hospital use, including all the drugs included in this study, and they are completely funded from the hospital budget. As these drugs are hospital-only drugs, they are procured through AMGROS who purchase medicines from manufacturers via a tendering process, which is the reason for real hospital drug prices not being publicly declared. The prices collected from the DKMA in this study represent the pharmacy retail prices declared by manufacturers and do not represent the real prices of purchase.
 
Cancer drugs costs are fully reimbursed to hospitals from the regional budgets through a national positive reimbursement list and patients obtain these drugs free of charge. If a certain drug is not on the positive list, an individual grant for funding could be granted for patients with approved special circumstances, upon a physician’s request. Although there is a reference pricing system for reimbursement, it is mainly for generic drugs and does not cover cancer drugs under patent protection.
 
Germany
 
The healthcare system in Germany is mainly funded by non-profit, quasi-public sickness funds which gather its financial resources from the mandatory SHI and covered 85.4% of the population in 2005. Healthcare is provided by a mixture of public and private providers following the Bismarckian Model. There are also private health insurance and two government schemes for civil servants to complement the predominant SHI system. Competition between sickness funds is encouraged by government regulation, but healthcare standards are governed centrally.
 
The Federal Joint Committee is responsible for allocating pharmaceutical products to reference pricing clusters, and restricting the use of certain drugs to particular indications. The Federal Associations of Sickness Funds set the reference price for all the clusters. The Institute for Quality and Efficiency (IQWiG) carries out health technology assessments on new health technologies, including drugs. Licensure of pharmaceutical is done by the Federal Institute for Pharmaceuticals and medical Devices (BfArM).
 
Pricing of pharmaceuticals in Germany follows different methods. In the hospital sector, hospital can negotiate drug prices with manufacturers and distributers, and they usually do so in cooperation with each other to gain more purchasing power. These prices are not publicly declared. In the ambulatory sector, prescription drugs, including cancer drugs, are priced according to statutory pricing as mark-ups are set for wholesalers and pharmacies, but not for manufacturers. As for non-prescription drugs, manufacturers, wholesalers and pharmacies are allowed to price their products freely. Pharmacy mark-up is € 8.10 flat fee plus 3% of the price for prescription drugs and reimbursable non-prescription drugs, with 19% VAT is added to the pharmacy retail price. Wholesalers are reimbursed according to a regressive scheme [2] that includes flat fees and percentages of manufacturer prices.
 
All prescription drugs are fully reimbursed under SHI, except those drugs that are included in a negative list. In the hospital sector, pharmaceuticals are reimbursed under the DRG system. Patients pay a co-payment of 10% of the drug price with a minimum of €5 and a maximum of €10. The extent of reimbursement is done according to reference prices which apply to all pharmaceuticals that are clustered in groups under the reference pricing system, with innovative drugs being exempt from reference pricing.
 
Hungary
 
Like Germany, the Hungarian healthcare system follows the Besmarkian model, where a SHI is in place, but the sources of funding come from both general taxation and SHI contributions, and it cover the entire population.
 
In general, the system is centralized in structure. The health insurance fund is managed by the Ministry of Finance, and the pharmaceutical policy is controlled by the Ministry of Health. The National Health Insurance Fund Administration (OEP) finances health services in Hungary, procures and reimburses pharmaceuticals, in addition to setting pricing procedures. The Technology Appraisal Committee advises the OEP on the reimbursement of pharmaceuticals.
 
All pharmaceuticals are priced freely at the manufacturer level regardless of prescription status. However, manufacturers negotiate prices of pharmaceuticals included in the reimbursement list with the OEP through a regulated process. Innovative drugs, in particular, are priced through external price referencing, where the price should not be higher than the lowest ex-factory price available in the reference country list. Pharmacy and wholesale margins are regulated by the Ministry of health and take the form of regressive markup scheme involving both fixed amounts and percentages of drug prices. A 5% VAT is added to the retail price.(51Due责任编辑:felicia)
 
Reimbursement of pharmaceuticals is done according to both a negative and a positive list of drugs determined by the OEP. Drugs in general are reimbursed according to a normative reimbursement process at different percentages of the pharmacy retail prices. Cancer drugs are fully reimbursed, but patients still have to pay a minor flat prescription fee of 300 HUF per package. It is worth mentioning that, unlike west European countries, most cancer drugs are obtained via prescription from community pharmacies, except those drugs that require hospitalization for administration, in which case reimbursement is done through a DRG system.
 
Latvia
 
The Latvian healthcare system is a centralized system funded from general taxation, with a large private sector that is mainly in the outpatient sector. The Ministry of Health is the central actor in Healthcare, and contains a Department of Pharmacy with which they form a legislative authority in the pharmaceutical sector. Authorization of pharmaceuticals is in the hands of the State Agency of Medicines, in addition to classification of pharmaceuticals, licensing of pharmaceutical businesses, and distribution of pharmaceuticals.
 
The State Medicines Pricing and Reimbursement Agency (SMPRA) is the body that makes decisions on pricing and inclusion of pharmaceutical on a positive reimbursement list. Prices of reimbursable drugs are determined through negotiations between SMPRA and manufacturers depending on the cost-effectiveness of the drug in question. Reimbursement of drug costs is determined through internal reference pricing, where drugs are compared to drugs with the same indication on the positive list, and external reference pricing, where prices should not be more than prices in other Baltic countries. Pharmacies and wholesalers are remunerated through a regressive mark-up scheme.
 
Reimbursement is carried out according to four disease state categories, where each category has a different reimbursement rate. Cancer drugs fall into the I category, designated to chronic, life threatening diseases and diseases that cause irreversible disability. In this category, all drugs are fully reimbursed.
 
Netherlands
 
SHI is the predominant funding system for healthcare in the Netherlands. There are several health insurance funds that provide an obligatory basic insurance package in addition to optional supplementary insurance. There are three main actors in pharmaceutical regulation system: the Ministry of Health, Welfare and Sport (VWS), who regulate pharmaceutical policy and controls pricing and reimbursement of pharmaceuticals, the Medicines Evaluation Board (CBG) who carries out health technology assessments, and the Health Care Insurance Board (CVZ), who work with the VWS on the reimbursement of pharmaceuticals.
 
The Dutch pharmaceutical pricing system is unique, it allows manufacturers to price their products freely, but imposes maximum prices for prescription-only drugs on wholesalers and pharmacies, which are set by the VWS and the Health Care Tariff Board (CTG). These prices are determined via external reference pricing which compares prices with those in Belgium, France, Germany and the United Kingdom. Wholesale margins are estimated at 13-24% of the ex-factory price, or 7-8% of the reimbursement price, excluding VAT.
(51Due责任编辑:felicia)

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