Nathan Jessop is a columnist for Pharmaceutical Technology Europe.

Nathan Jessop

Although the leading pharmaceutical companies are often termed multinationals, their regional origins are still important. Several studies have suggested that the idea of a global company that transcends national boundaries is an oversimplification of how businesses operate because such companies still retain many features of their national origin when expanding internationally. This effect is observed in the work culture that reflects operational decisions and a perceived preference for home-country nationals at the top of the organisation. This position is illustrated by GlaxoSmithKline, which originated in the UK. Although the company generates 96% of its sales elsewhere in the world, its British CEO, Andrew Witty, has reiterated that the company remains British and that it will maintain its main base in the UK despite the difficult operating environment (1). 

US pharmaceutical companies have tended to be high in the industry sales rankings. Therefore, as 2011 drew to a close, predictions that US company Pfizer was about to be displaced by French firm Sanofi as the world's leading pharmaceutical company in terms of sales came as a surprise and drew considerable media attention (2,3). After nine years of staying ahead of its rivals and being active on the merger and acquisition front, little evidence had indicated that Pfizer would be surpassed.  

Evaluate Pharma analysed companies' sales forecasts to 2016 and revealed the likelihood of a general shake-up in the rankings, with a number of European companies set to perform strongly against their previously dominant US rivals (4). The analysis suggested that by 2014, Pfizer would be the only remaining US pharmaceutical company in the top five. Pfizer is expected to slide to third, while Swiss companies Novartis and Roche will take second and fourth places, respectively. Meanwhile, GlaxoSmithKline will come in fifth, while US company Merck & Co. will slip to sixth, despite its $41-billion (€30.8 billion) acquisition of Schering-Plough in 2009.  

The major factor in Pfizer's commercial dip is considered to be the loss of US-patent protection for its blockbuster cholesterol-lowering statin Lipitor (atorvastatin), which occurred in November 2011. Launched in 1998, Lipitor reached peak sales of $12.9 billion (€9.7 billion) in 2006, accounting for 27% of Pfizer's revenue (5). In 2009, Pfizer acquired Wyeth in a $68-billion deal (€51 billion) to offset the impending loss of Lipitor's patent, but the product continued to represent a major source of sales; in 2010, Lipitor achieved sales of $10.8 billion (€8.1 billion), representing 15.8% of Pfizer's sales (5). 

The impending loss of patent protection led to India's Ranbaxy to develop a generic atorvastatin for the US and other markets. Starting in 2003, the company began launching patent challenges against Lipitor patents in several markets (6). Pfizer resisted strongly through its own legal counterattacks, but in 2008 it agreed to give Ranbaxy a license to sell atorvastatin in the US market, which became effective 30 November 2011. In addition, Ranbaxy will have exclusivity for 180 days before other companies can enter the market (6), while other agreements with Pfizer will also give Ranbaxy a license to sell atorvastatin in Canada, Belgium, the Netherlands, Germany, Sweden, Italy and Australia (6).  

The US is a key market for Ranbaxy, as it represents 70% of Pfizer's Lipitor sales (6). During its 180-day exclusivity period, Ranbaxy could generate as much as $650 million (€488 million) in sales. Ranbaxy also formed a partnership with Israel's Teva, which is the world's largest generic manufacturer. Teva has a strong distribution network in the US that should help Ranbaxy keep ahead of other competition such as Watson Pharmaceuticals, which is also seeking to introduce a generic version of atorvastatin.  

Although most attention has focused on Lipitor, Pfizer has several other products that have either recently lost patent protection, or will do shortly. Between 2010 and 2012, it was estimated that drugs representing 42% of Pfizer's pharmaceutical revenue were set to lose patent protection, including the antipsychotic Geodon (ziprasidone HCl), erectile-dysfunction drug Viagra (sildenafil citrate), overactivebladder drug Detrol (tolterodine) and eye-pressure lowering drug Xalatan (latanoprost ophthalmic solution) (5). 

Sanofi's rise in the rankings has been achieved through a steady focus on mergers and acquisitions, which started in 1999 with an allFrench tie-up with Synthélabo in a $30-billion (€22.5billion) deal (4). Then in 2004, while Novartis was still considering a bid for Aventis, Sanofi moved in to create Sanofi-Aventis in a $63-billion (€47billion) winning deal that the French government supported strongly to preserve jobs in France (7).  

Sanofi eventually dropped the name Aventis, thus signifying that it was the driving force within the merged company. In February 2011, Sanofi bought Genyzme with a $20.1-billion (€15.1billion) cash offer, which was seen as a shrewd move to replenish its R&D pipeline, due to Genyzme's strong biotech focus (8). In November 2011, Sanofi announced a 26% rise in third-quarter net profit, which included sales from newly acquired Genzyme. 

The manner in which the Genzyme acquisition went ahead has been contrasted with the way in which Sanofi took over Aventis. The Genzyme deal was very long and drawn out (taking 9 months), but Sanofi was the only company involved. It was obvious the merger would go ahead, but there were many negotiations over price. In contrast, there was never a clear cut regarding the winner of Aventis as the company had also been approached by Novartis (and there were rumours that GlaxoSmithKline was interested too) (1). The deal was about politics as well as price because a lot of outside players were involved, with the critical one being the French government. The SanofiAventis merger is often considered a messy affair because of the French government's heavyhanded intervention; French politicians were quoted as saying that they wanted to create a "national champion" (7, 9). In Europe, the final decision regarding mergers tends to rest with shareholders, whereas in the US, the directors have the major say. While the US process would not feature overt involvement from the government, the Genzyme merger shows that it can still result in a very long and drawn out process. 

Like Pfizer, Sanofi has faced its own patentexpiry challenges and has been scouring the market for a source of new revenuegenerating products. It lost a US patent challenge for its topselling blood-thinner product, Lovenox (enoxaparin), in a legal case in 2007 (1), and Sandoz, the generic arm of Novartis, has been selling a generic enoxaparin and eroding sales for Sanofi's product since 2010. In 2010, Sanofi generated around $30.1 billion (€22.6 billion)—around 7% of its revenue—from its anti-clotting drug Plavix (clopidogrel), which is marketed jointly with BristolMyers Squibb, but faces patent expiry in May 2012 (8). In 2006, Canadian generics manufacturer Apotex marketed a generic Plavix, but was ordered to halt production in November 2011. 

Interestingly, in September 2011, Pfizer agreed to let Sanofi sell a generic version of Lipitor in France (8). This agreement was part of a programme designed by France's Strategic Council of Health Industries, which fosters agreements between business and government. Such deals give the original manufacturer a tax break if it allows a genericsdrug manufacturer to produce and sell copies as the branded drug's patent expires. Specifically, the French government hopes that this will keep local production sites open and boost employment (10). 

Regarding future growth, another area Sanofi sees as important is emerging markets. In 2010, Sanofi's emergingmarket sales rose by 16% (11). However, some have criticised the company as being too optimistic. In 2011, Sanofi admitted that it had underperformed in Turkey due to "significant price decreases", as well as in eastern European markets because of the ongoing economic crisis (10). Even so, the company retains faith in emerging markets, pointing out that 2010 sales increased by 47% in China and by 19% in Brazil (11). 

The idea that European pharmaceutical companies are set to outperform their US counterparts should be welcome news to politicians, who are eager for the pharmaceutical industry to continue to invest in Europe. According to the European Federation of Pharmaceutical Industries and Associations (EFPIA), the European pharmaceutical industry represents 19.2% of total EU private R&D expenditure and 3.5% of EU manufactured exports (12). For several years, EFPIA has been lobbying European politicians to move away from harsh costcontainment approaches and to create a friendlier environment for the pharmaceutical industry, particularly as some companies have chosen to make new investments elsewhere, such as in the US or emerging markets. Between 1990 and 2008, for example, R&D investment in the US grew 5.6 times, compared with only 3.5 times in Europe (12). 

Whether Sanofi's surge to the top of the rankings, followed by some of its European colleagues, represents a true strengthening of European pharmaceutical competitiveness is hard to say. Pharmaceutical companies remain unhappy with operating conditions in Europe, even if they have their origins in the region. Over the next couple of years, it will be interesting to see whether European companies such as Sanofi, GlaxoSmithKline, Novartis and Roche decide to increase their investment in Europe now that their future financial performance looks promising.  

1. A. Clark, "Big firms have allowed themselves to be seen as detached from society" (The Guardian, 2011). 

2. T. Staton, "Sanofi set to rev past Pfizer in pharma rankings" (FiercePharma, 2011). 

3. K. Grogan, "Sanofi to topple Pfizer as sales league leader next year" (PharmaTimes, 2011). 

4. Evaluate Pharma, "Pfizer to lose crown to Sanofi as world's biggest drug maker" (2011). 

5. M. Alazraki, "The 10 Biggest-Selling Drugs That Are About to Lose Their Patent" (Daily Finance, 2011). 

6. Ranbaxy, "Ranbaxy and Pfizer settle Lipitor litigation worldwide" (2008). 

7. BBC News, "Aventis and Sanofi set for merger". (2004). 

8. Reuters, "Sanofi to buy Genzyme for more than $20 billion" (2011). 

9. The Pharmaletter, "Agreement on Sanofi-Aventis/Genzyme deal prompts lawyer comment on Europe/USA differences on takeovers" (2011). 

10. K. Grogan, "Sanofi signs deal with Pfizer to sell generic Lipitor" (PharmaTimes, 2011). 

11. A. Torsoli, "Sanofi May Be Too Optimistic in Emerging-Markets Forecast" (Bloomberg, 2011). 

12. EFPIA, "Improving Europe's competitiveness" (2011). 

Articles

The next two years may see a shake up in the world's current top pharmaceutical companies, with Pfizer likely to be the only US firm to remain in the top five by sales.

European Pharma Companies Set To Surge Ahead Of US Rivals

By 2025, more than 20% of the European population will be 65 or older, with a particularly rapid increase in the number of people over 80. By 2050, the number of people aged 65 and above is expected to grow by 70% and the number of people aged over 80 by 170% (1). 

Nathan Jessop ((Spotlight image) Stockbyte/GettyImages) 

In 2004, the US National Center for Health Statistics reported that 80% of the elderly population (adults aged 65 years and older) took at least one prescription drug in the prior month. Its survey revealed that around half of the individuals in the same age group reported taking three or more prescription drugs and that this statistic represented an increase of nearly 50% over the prior 5–10 years (2). The issue of polypharmacy is also of particular concern in the elderly, who, compared with younger individuals, tend to have more disease conditions for which medicines are required (3). While pan-European figures are hard to come by, these insights into trends in healthcare usage by the elderly studied elsewhere in the world should be considered relevant for the future of healthcare in Europe. 

The European Commission's (EC) official position is to actively support Member States in their efforts to promote healthy ageing through dedicated initiatives to improve the health of older people. An ageing population in good health will also mean less strain on health systems and fewer people retiring from work due to ill health. At present, the European Innovation Partnership on Active and Healthy Ageing aims to ensure that the average European citizen has two more active and healthy years to live by 2020 (4). The EC have termed ageing as an opportunity for the region rather than a hindrance. The Partnerships Steering Group was set up in May 2011, and is made up of more than 30 stakeholders representing the health and ageing area, including Member States and regions, organisations representing older patients, nurses, carers and doctors, hospital representatives, academics, industry and venture capitalists organisations. It has already announced that in 2012, it will launch calls for involvement of stakeholders beyond those that participated in the Steering Group to implement together the priorities and actions identified in a Strategic Implementation Plan that it adopted at a meeting in November 2011 (4). 

While those behind the initiative push the project forward, their optimism sits in contrast to the current realities because funding and resourcing healthcare systems through societies with smaller workforces is becoming extremely difficult. Most governments have no choice but to make cutbacks in the current, uncertain economic environment, which affects the ability to deliver effective healthcare services for the growing elderly population. For example, the EU recently and dramatically revised its growth forecast for the Eurozone in 2012, from 1.8% to a mere 0.5% (5). Such financial predictions will do little to convince nervous politicians to provide additional investment for initiatives to boost healthcare systems that are already underfunded.  

The ominous situation in Greece illustrates the difficulties that can arise in the current economic climate. As a result of the economic meltdown, doctors' wages in the public system have been cut in line with those of other government workers, and hospitals are at risk of being merged and face regular shortages of materials. Even patients who should be entitled to reduced or free medication often cannot find pharmacists to provide them and are instead asked to pay the cost up front and then seek reimbursement. 

Inadequate representation of the elderly in clinical trials

While the elderly account for high drug consumption, they remain underrepresented in clinical trials. A number of European geriatricians have gone as far as to launch a charter against ageism in clinical trials, highlighting that practical issues in involving elderly people in clinical trials are not the only reason for such observations. These views are the result of their involvement in the European-wide PREDICT consortium for "Increasing the Participation of the Elderly In Clinical Trials" (6). Coordinated from the Medical Economics & Research Centre, Sheffield, UK, the PREDICT initiative began in February 2008 and has received support from the EU and FP7 Health research (the Seventh Framework Programme of the EU for the funding of research and technological development in Europe). The aim of PREDICT is to investigate reasons for the exclusion of the elderly in clinical trials and to provide solutions for this problem. Those behind PREDICT highlight that an analogous problem occurred in the paediatric population, but research in this domain has considerably improved and therefore offers an example of what can be achieved. 

Several key European geriatricians state that they have often found themselves in a situation where they were unable to offer patients the best course of treatment with the weight of scientific evidence behind them because of insufficient evidence from clinical trials (6). The group has also carried out extensive reviews of medical literature for conditions prevalent in elderly people to back their opinions. In 2010, PREDICT researchers reported findings from interviews with health professionals in nine countries, as well as from more than 50 focus groups with elderly people and their carers. More recently, it published some of its conclusions in a peer-reviewed paper in the 

, focusing primarily on the extent of exclusion of older individuals in ongoing clinical trials regarding heart failure (7). 

The EMA has also taken account of the demographic implications of ageing. In October 2011, it issued an invitation for expressions of interest in an EMA workshop on medicines for older people (8). The provisional dates stated for the workshop are March 22–23, 2012. The workshop will feature a presentation and discussion of the EMA geriatric medicines strategy and related activities, so that gaps in the strategy can be identified. The EMA hopes that a presentation of its strategy in this field will provide opportunity for the identification of synergy areas between stakeholders. It will also seek input on the regulatory mechanisms it is developing to boost geriatric medicine. The sessions currently planned focus on themes that match the EC's European Year of Active Ageing initiative, namely healthy ageing and medicines, demonstrating safety and efficacy in the older population, geriatric pharmacovigilance, and the role of regulatory agencies in providing information to the older population. 

Opportunities for the pharmaceutical industry

For the pharmaceutical industry, a renewed focus on the elderly population offers a tremendous research and commercial opportunity. The work of the PREDICT group and the EMA should also help companies to trial their drugs in this underserved section of the population.  

It is predicted that the Alzheimer's disease drug market will nearly triple over the next 10 years, increasing from €4 billion in 2010 to €10.6 billion in 2020 in the major markets of the US, France, Germany, Italy, Spain, the UK and Japan (9). At present the market is dominated by symptomatic therapies that only provide modest effects on cognitive and functional decline but there is a need for more effective drugs. To date, governments have been unwilling to fund expensive new therapies. For example, the UK's National Institute for Clinical Excellence (NICE) caused considerable patient anger in 2007 when it ruled that Aricept and similar drugs should be restricted to people whose dementia had progressed from mild to the moderate, but has not yet reached severe (10). The pharmaceutical industry must find natural allies among patient organisations and clinicians who are dissatisfied with the availability of treatments for elderly section of the population. If governments have publicly stated that they will back initiatives to improve healthcare for the elderly, then their commitment to reimbursing new therapies will be expected. 

Companies are aware that pricing will remain important and in the US market, which is becoming more cost conscious, many firms are attempting to become more proactive. For example, Pfizer recently signed a five-year agreement with the US healthcare insurer Humana to investigate treatment costs for the elderly in chronic pain, cardiovascular disease and Alzheimer's disease. The two companies will look at products in relation to healthcare resources and reducing costs (11). The Pharmaceutical Research and Manufacturers of America (PhRMA) industry body has highlighted the cost of failing to treat chronic diseases, estimated it to be as much as 75 cents of every dollar spent on healthcare in the US (12). 

Europe faces serious challenges in sustaining its healthcare systems to deliver high quality services to the elderly. Initiatives are being launched at a European level and have received high profile backing from the EC, the EMA and key geriatricians. Such an approach has led to improvements in addressing the gaps seen in paediatric medicine and is seen as a potential model for making improvements with respect to the elderly. Sadly, the ongoing economic difficulties in Europe may hinder investment in additional healthcare services for the elderly as politicians look to implement cutbacks. However, the elderly also represent a growing proportion of the voting population and will therefore not accept their long-term healthcare needs being ignored. For the pharmaceutical industry the demographic trends present opportunities to launch new therapies in these disease areas. 

3. P.A. Rochon et al., "Drug prescribing for older adults," UpToDate (2011).  

4. EC, "European Innovation Partnership agrees on actions to turn ageing into an opportunity," Press Release (2011).  

5. BBC News, "Eurozone's growth has stalled, says EU," (2011). 

6. PREDICT, "Increasing the participation of the elderly in clinical trials," (2011). 

8. EMA, "EMA workshop on medicines for older people," (2011). 

9. Decision Resources, "The Alzheimer's disease drug market will nearly triple over the next ten years," (2011).  

10. A. Palmer, "It's not Nice… but the alternative is worse." (Daily Telegraph, 2007). 

11. Inpharm, "Pfizer has signed a five-year research pact with US healthcare insurer Humana," (2011). 

12. G. Forrer, "Treating chronic disease could help forestall onset of Alzheimer's disease," (PhRMA, 2011). 

Despite the fact that Europe's population is ageing rapidly, the region is astonishingly still underprepared for dealing with the health-related effect of this demographic trend.

Impact of Ageing

Cardiovascular disease is a major health threat in Europe. Every year, cardiovascular disease accounts for 23% of Europe's disease burden and is responsible for nearly half of all deaths (48%) in the region (1). Major risk factors include diet, obesity, diet, smoking, physical inactivity, alcohol consumption, high blood pressure and high cholesterol.  

Recent health statistics have renewed concerns that the situation is worsening (1). For example, obesity and physical inactivity have often been linked to adult lifestyles, but these risk factors are now routinely being observed among children. According to the European Heart Network, almost 20% of children in Europe are overweight or obese (2). Similarly, although public perception of heart disease mainly focuses on men, women are also increasingly affected; indeed, cardiovascular disease is the main cause of death in women in all European countries (1). One contributory factor is that a previously seen decline in smoking across Europe appears to have slowed and that women now smoke nearly as much as men.  

Not surprisingly, cardiovascular disease has a huge economic impact in Europe. The cost to the EU economy has been estimated at €192 billion a year, with around 57% of this related directly to healthcare costs, 21% to productivity losses and 22% to the informal care of people with cardiovascular disease (1). 

European policymakers, regulators, the medical community and patient groups alike are alarmed at the impact cardiovascular disease has had in the region and in recent years there has been increasing cooperation between countries to lessen the threat. Part of this cooperation has involved raising the profile of World Heart Day. Created in 2000 by the World Heart Federation, World Heart Day is an annual event held on 29 September to inform people that heart disease and stroke are the world's leading cause of death. In Europe, this year's event was backed by the EMA, which worked together with other organisations representing patients. A number of pharmaceutical companies, including AstraZeneca, Pfizer, Sanofi, Bayer and Boehringer Ingelheim, also supported the 2011 event.  

This year's event centred on individuals to drive home the importance of healthy lifestyles (3). People were encouraged to visit their doctor and have their blood pressure, cholesterol and glucose levels, waist-to-hip ratio and body mass index assessed. The campaign also featured a "know your numbers" theme to make people more aware of their risk of developing cardiovascular disease and the need to develop a personal action plan. The World Heart Federation also encouraged companies to become involved by educating their employees in the workplace. The organisers emphasised economic arguments and highlighted the financial benefits for companies of having a healthier workforce. 

The EMA plays an important role in the authorisation of medicines to treat heart disease and stroke and has used this position to become more directly involved in initiatives, such as World Heart Day, as a means to lessen the healthcare burden of cardiovascular disease. It also has an important role in providing guidance to the pharmaceutical industry and to users of its cardiovascular products, and organises regular events and meetings for stakeholders. In late 2010, for example, the EMA set up an expert group meeting on paediatric heart failure. The group's objectives include the optimal design of studies on drug development in paediatric heart failure, developing a priority list of pipeline drugs in this field and establishing a wider paediatric cardiology network. In terms of high-profile cardiovascular guidance projects, in September 2011, the EMA began finalising its benefit–risk review of Sanofi's anti-arrhythmic medicine Multaq (dronedarone) after two patients taking the medicine experienced liver damage in January 2011. In the US, Sanofi took note of this development and sent a letter to healthcare professionals to suggest considering periodic liver-function tests in patients taking Multaq (4). The FDA reacted by issuing its own safety announcement while the EMA began to independently review the data. By July 2011, the scope of the EMA review had been extended to look at emerging data related to the effects of the medicine on the heart, blood vessels and lungs. Due to the seriousness of the situation, the EMA held additional meetings outside of its normal schedule. 

The EMA has also been collaborating with the European Heart Network (EHN) with respect to World Heart Day. The EHN is an alliance of heart foundations and nongovernmental organisations throughout Europe, with member organisations in 26 countries. Using advocacy, networking, education and patient support, the EHN seeks to play a leading role in the prevention and reduction of cardiovascular diseases. The EHN believes that 80% of current cases of cardiovascular disease can be prevented and that even small reductions in incidence and mortality will result in large health gains and reductions in direct and indirect healthcare costs (5). With this in mind, EHN and the European Society of Cardiology created a joint project called EuroHeart. The project involves partners in 21 countries in the EU and the European Economic Area, and receives funding from the European Commission Public Health Programme. The first EuroHeart ran from April 2007 to March and focused on five core areas, including the impact of cardiovascular disease on women and the implementation and adaptation of European guidelines on disease prevention to national situations. EuroHeart II is now underway and will analyse the current situation regarding cardiovascular disease in the EU with the goal of developing a long-term strategy. In particular, the EHN is keen to develop measures for less-advantaged groups. 

The fight against cardiovascular disease now has a high political profile thanks to the EHN and European Society of Cardiology. These two organisations manage the Secretariat for the Members of the European Parliament (MEP) Heart Group. This forum is made up of MEPs who have an interest in promoting measures to tackle the threat of cardiovascular disease. Several of the members have a medical background, although there is no restriction on the MEPs who can become involved. The group has been heavily involved in raising the profile of World Heart Day at a political level to influence EU health policy. In March 2011, the MEP Heart Group held a meeting to examine how e-healthcare initiatives could be tailored for cardiovascular disease. Its October 2011 meeting examined how learnings from the United Nations Summit on NonCommunicable Diseases could be applied to the group's own objectives. 

For the pharmaceutical industry, cardiovascular disease is an important commercial target for treatments and diagnostic tools. Typically, the cardiovascular therapeutic area comprises around 15% of the total pharmaceutical market (6), and Europe's political, regulatory and medical emphasis on improving the outlook for cardiovascular health should create further opportunities for companies to market products in this therapeutic area. Despite the expected demand, however, pharma companies are concerned that cost pressures and cautious regulatory approaches will stand in the way of innovative therapies. It is also unlikely that the EMA's ongoing Multaq review will add to the industry's confidence. 

At the 2010 European Society of Cardiology's annual meeting, the organisation's president, Roberto Ferrari, was cited as implying that cardiology had become a victim of its own success (7). Although noting that therapeutic advances in cardiovascular medicine had increased average life spans by about 7–10 years, he also added that regulatory demands were increasing, particularly regarding the required size of clinical trials; large-scale trials inevitably drive up the expense of the development programme. One fear expressed was that companies might choose to reduce investment in the cardiovascular area and preferentially focus on therapy sectors seen as more profitable, such as oncology. 

But it's not all bad news on the regulatory front regarding pharmaceutical innovation in this therapy area. Since 2006, the European Federation of Pharmaceutical Industry Associations (EFPIA) has been working with the EMA to develop reliable biomarkers for cardiovascular drug development and in 2009, a workshop was held to discuss the possibilities (8). As biomarkers represent substitutes for clinically meaningful endpoints, their regulatory acceptance would revolutionise cardiovascular drug development by shortening development times. Potential candidates fall into three areas: laboratory markers, physiological parameters and imaging biomarkers. Current thinking is that a cluster of biomarkers will be needed to make progress, as well as collaboration between the pharmaceutical industry and EMA. Fortunately, it does appear that both sides are eager to cooperate and this bodes well for the development of new cardiovascular therapies in line with public health objectives. 

1. European Heart Network, "Cardiovascular Disease Statistics" (2011). 

2. European Heart Network, "Children and Obesity and Associated Avoidable Chronic Diseases" (2011), 

3. World Heart Federation, "World Heart Day" (2011), 

4. L. Nainggolan, "FDA Alert: Dronedarone and severe liver injury", 

Pharmaceutical Market Trends, 2010–2014 

7. EFPIA, "Enlightened self-interest delivering wider insights?", blog post, (2010), 

8. Gonzalo Calvo, "Cardiovascular Biomarkers: A Regulatory Perspective", Presentation from the EMEA/EFPIA Workshop On Biomarkers (2009). 

With the cardiovascular disease burden in Europe increasing, policymakers, regulators and other healthcare stakeholders are seeking to raise awareness and lessen the threat.

Threats and Opportunities in Cardiovascular Health

With underlying technologies advancing, there has been a drive in recent years to introduce electronic prescriptions. Although electronic prescribing has gained popularity in the US and been explored by a few countries in the EU, such as Sweden, Denmark and the Netherlands, it's widespread acceptance in Europe is still pending, particularly as official backing has been unclear.  

This situation looks likely to change. The EMA's Unit for Information and Communications Technology recently issued a request for expressions of interest from softwaredevelopment companies to participate in a workshop, scheduled to be held at the beginning of October, on the future of electronic prescribing in the EU (1). The outcome, once published, will provide important insight into how the agency will regulate the area of electronic prescribing. As any changes in the way prescriptions are handled will impact all stakeholders within healthcare, the EMA also extended its workshop invitation to physicians, pharmaceutical purchasers, patient representatives, health-technology-assessment bodies, specialists in the safety of medicines, experts in quality monitoring of healthcare, regulators and representatives of the pharmaceutical industry. Members of the EMA's electronic summary of product characteristics (e-SPC) project will be the main representatives from the agency's side. The e-SPC project has been examining how the information regarding authorised medicines that appears in summaries of product characteristics can be structured to better relate to available and emerging electronic media. The hope is that by understanding prescribers' information needs and providing a means to supply it electronically, the prescribing process can be better customised for individual patient needs, while also improving safety and effectiveness. 

Much attention in the area of electronic prescribing inevitably centres on technologies emerging in daily life, such as faster internet connections, iPads and voice-activated control systems, that might be harnessed for the purposes of heathcare. However, focus also needs to be broader for electronic prescribing to stand any chance of success. Technology cannot just be looked at in isolation and needs to be customised to suit the situation and the people who will be using it. You can't just throw a gadget at something and hope that it solves all your problems! Thus, electronic prescribing cannot just be a simple tool that delivers prescriptions in an electronic format; it must integrate into the existing healthcare system, making it more secure and reliable as a result of the electronic decision-making database systems employed.  

Electronic prescribing has several potential advantages; for example, it could provide a means to crosscheck on double medication, contra-indications and dosage at the moment of prescribing. In particular, much has been made of the potential an electronic approach offers in reducing the number of medical accidents due to prescribing errors. In a litigious country such as the US, this potential benefit is a highly topical subject and has contributed towards greater acceptance of the electronic prescribing concept. For example, one US legal firm cites figures stating that 7000 people lose their lives due to prescription mistakes annually and that more than 100000 people are affected by prescription mistakes each year (2). A 2007 report by CNN also stated that an estimated 30 million dispensing errors out of 3 billion prescriptions annually occur at outpatient pharmacies in the US (3). There is also a concern that prescription errors are increasing. This is partly due to the wide array of drugs now on the market, some of which have similar names, and a greater reliance on healthcare services taking place outside the hospital. 

In Europe, it is much harder to get a picture of how widespread this problem is, but some information is available for individual countries. In the UK, a 2009 report commissioned by the General Medical Council (GMC) suggested that almost 1 in 10 prescribed items in hospitals had errors associated with them (4). The study involved hospital pharmacists in 19 hospitals in North West England. Out of 124260 medication orders checked by pharmacists within the study hospitals over a predefined period, 11077 errors were detected (6). Of these, 2% were classified as potentially lethal (4). Worryingly, errors were made by all grades of doctors, including consultants. Nearly all these errors were reportedly intercepted by pharmacists before the patients received the medicines prescribed. In a separate part of the study that examined qualitative factors in prescribing, many doctors stated that they relied heavily on pharmacists and nurses to identify and correct prescribing errors. In effect, they believed that pharmacists provided an important safety net to prevent patients receiving the wrong medication. For example, if a system links up to a patient database, it may be able to provide details about medicines that specific patients need to avoid because of interactions with other drugs. In addition, if a doctor mistakenly prescribes a medicine that could potentially interact with another, the electronic system could immediately flag up a warning.  

The European leaders in electronic prescribing are Sweden and Denmark, but the concept is gaining momentum in the Netherlands. In 2002 the Dutch government established the National IT Institute for Healthcare (Nictiz) to introduce IT solutions into the field of healthcare. Nictiz initially focused on gathering the medication history of patients based on dispensing information retrieved from community pharmacies. It has now implemented solutions for electronic prescribing, but has acknowledged difficulties in convincing all physicians of the benefits of the system.  

Despite this, most general practitioners in the Netherlands now register their prescriptions electronically. Patients tend to first be treated by a GP before being referred to specialists, and Nictiz has noted that it is the specialists giving the consultation who often still seem reluctant to use electronic devices to enter patient data. There could be several reasons for this. Doctors may feel as if they are losing control by handing everything over to an electronic system, or they could be way about the promises of electronic systems, which largely remain untested on a wide scale. 

In the Netherlands, electronic prescriptions will be equipped with an electronic signature from the prescriber, which will make the paper version obsolete. European legislation requires a signature to be on a prescription, but Dutch law has been amended to accept an electronic signature as valid from a recognised prescriber. As well as improving the acceptance of electronic prescriptions, it is necessary to have adequate intervention systems in place. Although the telephone still acts as an emergency option, the hope is to have electronic intervention systems that can automatically flag anomalies. The speed of such systems is critical. For example, when patients have been discharged from the hospital, it will be important that medication instructions do not get overlooked as their care is transferred to others outside the hospital. 

Other countries in the EU are only cautiously exploring electronic prescribing. For example, an electronic prescriptions project was launched in April 2011 by the Czech State Institute of Drug Control, but the system seems only electronic in name as each prescription tends to be accompanied by a paper version. Czech health insurance funds do have no access to the electronic prescription system, which means they are unable to check that a particular prescription was actually filled by a doctor. Consequently, this affects reimbursement decisions for the medicine, but Czech health insurance law is currently being amended to close this gap. To date, the electronic prescription system has only been used by eight doctors and eight pharmacies, with 512 electronic prescriptions issued, but the entire project has cost more than €6.99 million (5). The Czech situation illustrates the need for an approach to electronic prescribing that takes into account all stakeholders in healthcare, which is why the EMA has made efforts to include a wide range of participants in their workshop. 

Electronic prescribing has important implications for the pharmaceutical industry because it will represent a change in physician behaviour. Pharma companies will need to determine how this trend will affect the prescribing of their products and ensure they provide physicians with adequate support (9). To maintain relationships with physicians, companies will need to be seen as experts in the electronic prescribing field themselves. In the US market, pharmaceutical companies have had to adapt very quickly to changes in physician attitudes and assess the strategy of their sales representatives who interact with physicians. In 2007, only 6% of physicians were prescribing electronically, but by 2010 this had jumped to over 30% (6)—and financial incentives from the US government to drive uptake mean that this trend will increase.  

In Europe, although there has been discussion of the issues around electronic prescribing, there are few obvious signs that the pharma industry is preparing for large-scale uptake. It is inevitable that it will be eventually adopted, but no timeline can be predicted at the moment. The EMA's workshop will provide important direction to those interested in the concept and provide an official framework for the field to develop. Based on these outcomes, the European pharmaceutical industry will need to rapidly adapt to the changing prescribing environment. However, its knowledge of markets where electronic prescribing has proved a success should provide suitable experience to deal with changes in the European healthcare environment. 

1. EMA, "Software development companies invited to express interest in workshop on electronic prescribing", News Release (UK, 2011).  

2. Whitener Law Firm, P.A, "Prescription mistakes" (US, 2011). 

3. E. Cohen, "Don't be a victim of pharmacy errors", CNN (2007). 

4. Guild of Healthcare Pharmacists, "Pharmacists EQUIP doctors with safety net when it comes to prescribing in hospital" (2009). 

5. PMR, "Czech e-prescription system paperless only in name" (2011). 

6. E. John. "Pharma must prepare for e-prescribing closeup", Medical, Marketing & media (2011). 

Electronic prescribing has grown strongly in the US but its future as a European-wide approach in healthcare has been uncertain; new regulatory interest could change the playing field.

Europe Edging Towards Electronic Prescribing

Over the past 30 years, there have been dramatic advances in many areas, including biotechnology, genomics, diagnostic imaging, molecular diagnostics, organ and tissue replacement, surgical techniques, wound care and computer technology, which have led to improved healthcare delivery and patient outcomes (1). Patients and physicians alike want access to these latest treatment options, but many have little regard for the cost involved and assume that these new technologies should be funded automatically. Governments have introduced cost-containment measures to slow healthcare spending, but remain wary of public opinion when making decisions about which treatments should receive funding. Of course, no government wants to be accused of overtly placing cost restrictions on healthcare, particularly as this is likely to lose them votes in an election. In Europe, during the early 1990s, the word 'rationing' began to be introduced in the field of healthcare, but politicians began to steer away from this terminology because it was found that voters tended to believe that 'rationing' was somehow depriving them of their basic rights (2). 

To manage the demand for expensive treatments in a more controlled way, governments have become increasingly reliant on healthcare technology assessment (HTA). HTA is a multidisciplinary field of policy analysis, and studies the medical, social, ethical and economic implications of development, diffusion and use of health technology. In principle, HTA is supposed to assist payers in making informed decisions about allocating resources (including expenditure on medicines) in the health system and its supporters believe that it better links medical innovation to the actual needs of the healthcare system (3, 4).  

Many countries, both in Europe and elsewhere in the world, have dedicated HTA review bodies. HTA uses a number of different disciplines to assess the benefits and, in some cases, costs of a given medicine. A large number of stakeholders are involved, and HTA bodies typically include epidemiologists, economists, physicians, pharmacists, healthcare managers and, increasingly, patient group representatives (3, 4). 

Pharmaceutical companies, however, remain unconvinced that HTA results in an appropriate decision being made. Critics have argued that a poorly designed or managed HTA risks denying patients appropriate access to medical technologies, and can also restrict clinical freedom and lead to a waste of important resources (4). HTA approaches that target high-priced drugs also send distorted signals to medical innovators and remove the incentive to research new therapies (4). Companies developing new drugs have to recoup their initial R&D investment and commercialisation costs, and have no alternative but to set high prices for their products. According to the Tufts Center for the Study of Drug Development (CSDD), the cost of developing a new drug averages at about €2.1 billion (5). 

One example of the frustrations that the pharmaceutical industry has had with HTA is illustrated by its dealings with the UK's HTA, the National Institute for Health and Clinical Excellence (NICE), which frequently recommends against the adoption of new drugs. Only last month (August) for instance, NICE decided not to recommend payment for Novartis' multiple sclerosis (MS) drug Gilenya (fingolimod). NICE's provisional guidance stated that there were uncertainties over the clinical effectiveness of the drug and that the evidence available did not suggest that it would be a costeffective use of healthcare system resources (6). As well as angering Novartis, the decision attracted complaints from MS patient organisations, with the UK's MS Society being quoted in the media as stating that MS patients would be better off living almost anywhere else in Europe than in the UK because of the poor access to treatments (6). For Novartis, this was another setback with NICE. In April 2011, the body had refused to recommend, on appeal, its kidney cancer drug Afinitor (everolimus). 

The controversies regarding NICE have impacted other emerging European HTA bodies, which are immediately viewed with suspicion by both patients and the pharmaceutical industry. This negativity has not gone unnoticed; for example, from its statements, Germany's Instituts für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) HTA seems keen to distance itself from any direct comparisons with its UK counterpart (7). IQWiG admits to cooperating with NICE and other European HTA bodies, but stresses the differences between methodologies and that inter-agency discussions examine to what extent methods might be compatible (9). France's Haute Autorité de Santé (HAS) has also stated that differences remain in methodologies between European HTA bodies (10).  

At present, HAS is struggling to justify its role because it has been caught up in France's domestic controversy regarding Servier's Mediator (benfluorex) drug, which may have caused the deaths of as many as 2000 people (10). The scandal has implicated both Servier's representatives and the French health authorities. In 2010, HAS issued a press release to defend itself, but the agency has been accused of contributing to the errors that led to Mediator staying on the French market (11). One critic of the Mediator situation recently wrote in the 

that a French government report appeared to omit details of HAS's contribution to decision-making regarding the drug (12).  

Despite the difficulties that individual HTA bodies might face, there is growing cooperation between counterparts in different countries, but this is a concern for pharmaceutical companies. Recently, a number of international industry representatives commissioned consulting firm Charles River Associates to conduct a comparative assessment of the role and impact of HTAs in different parts of the world. Key industry bodies that backed the report included the European Federation of Pharmaceutical Industries and Associations (EFPIA), the Pharmaceutical Research and Manufacturers of America Medicines Australia and EuropaBio (4). EFPIA has stated that it hopes the report will form the foundation of future, regular exercises to monitor HTA (13). 

The authors of the study noted that although there were many reports on the workings of HTA bodies in different countries and how they were evolving, there was relatively little public domain information on the impact of their decisions. In particular, little had been published about whether the outcome of HTA related to the assessment of the value of the medicine, the type of HTA, or whether decisions really did result in a superior allocation of scarce health resources (5). A major conclusion of the study was that although HTA was supposed to improve access to innovative treatments, there was little evidence that current HTA processes were speeding up access. Furthermore, the study authors stated that recommendations from HTA bodies were not always implemented by pricing and reimbursement authorities. In general, the link between HTA and pricing and reimbursement was far from clear, and decisions over the same product varied greatly between systems and countries.  

The authors acknowledged that the remit of the HTA bodies was different in countries surveyed, but were concerned that these bodies were reaching very different decisions over the same products. They suggested that the lack of consistency pointed to inefficiencies in HTA processes and weaknesses in their methodology. In particular, they were unimpressed at the differing data requirements to reach decisions. The study revealed that most HTA systems considered data from published randomised clinical trials as the preferred evidence for evaluation, but countries varied on consideration of other information (5). Clearly, divergent opinions were found as to whether HTA should include a full assessment of societal value.  

At one extreme were bodies such as NICE, which only take into account the impact of a technology on public healthcare resources. At the other extreme, only the HTA systems in Sweden and the Netherlands were found to consistently consider societal value for cost-effectiveness analysis (4). Some other countries did have provisions to allow societal value to be considered, but guidance appeared vague. In Poland, for example, HTA guidelines stress that the first consideration for any analysis should be that of the healthcare system, but adopting a social perspective may be justified in some cases, such as where the health effects of a particular technology impact members of society other than the patient (4). Not surprisingly, however, the study authors found few examples of non-healthcare costs or benefits having been taken into consideration in evaluations, even where the HTA system allowed for their inclusion. In the Netherlands and Sweden, where a societal perspective is used, the societal information considered is not described in the final evaluation report. The pharmaceutical industry continues to believe that societal value is an important component of any HTA to efficiently allocate available resources. In line with this thinking, the industry has been in favour of involving patients more in HTA bodies (13). 

Despite their unpopularity with pharmaceutical companies and, in many cases, with patient groups and physicians as well, HTA is an established part of healthcare systems worldwide. To date, HTAs in different countries have evolved in isolation to each other, which makes analysis of their impact difficult. The recently published international analysis of HTA processes suggests that the pharmaceutical industry will be less passive in how it approaches HTA decision-making. Publications of this nature will better enable companies to challenge the approaches being used by HTA bodies. 

 C.S Goodman, "HTA 101: Introduction to Health Technology Assessment" (National Information Center on Health Services Research and Healthcare Technology, US National Library of Medicine, National Institutes of Health, January, 2004), 

A Comparative Analysis Of The Role And Impact Of Health Technology Assessment

 C. Sorenson, M. Drummond and P. Kanavos, 

The Role Of Health Technology Assessment In The European Union. The European Observatory on Health Systems and Policies

 Tufts Center for the Study of Drug Development, "Drug Developers Are Aggressively Changing the Way They Do R&D", Press Release (MA, USA, 2011). 

 K. Grogan, "Uproar over NICE rejection of Novartis MS pill", 

 International Society for Pharmacoeconomics and Outcomes Research (ISPOR), "The German IQWiG — It's Not NICE Benefit Assessment in Germany — New Sense or Nuisance?" 

 International Network of Agencies for Health Technology Assessment (INAHTA), "IQWIG — Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen" 

 Haute Autorité de Santé, "Le NICE, l'IQWIG et la HAS concluent un accord de coopération", Press Release, (France, 13 April 2006). 

 Haute Autorité de Santé, "Mise au point de la Haute Autorité de Santé sur Mediator", Press Release, (France, 1 December 2010). 

 EFPIA, "New Study on HTA Processes Highlights Areas for Improvement to Accelerate Patients' Access to Innovative Medicines", Press Release (Belgium, 13 July 2011).London, UK 

The rising cost of healthcare has complicated the introduction of new, innovative drugs and other medical technologies. While the medical impact of these healthcare advances cannot be denied, governments and healthcare policy makers have found it difficult to sustain the funding of these expensive treatments.

Health Technology Assessment Under Scrutiny

Following recent discussions, the EC has decided to support Croatia's entry into the EU. Croatia originally applied for membership in 2003, with formal discussions beginning in 2005, but progress faltered over time because of issues regarding the legal system and environment for competition (1). Bulgaria and Romania, which joined the EU in 2007, had previously failed to meet full EU standards in these areas, and their pre-accession environment was believed to be similar to that of Croatia. As a result of political and media criticism of these countries' ease in gaining entry, there was greater scrutiny of Croatia and a general reluctance to fasttrack the application. In particular, there were worries concerning corruption and organised crime in the country. It now appears that these concerns have been overcome, so Croatia is set to become the 28th member of the EU in 2013. 

The Croatian pharmaceutical market is currently worth around €740.1 million and has been growing slowly because of the government's ability to fund healthcare as a result of the global economic crisis (2). In the short term, the market is considered challenging for manufacturers of branded products because of the prevalence and popularity of generic drugs, and strict reimbursement criteria. However, in the longer term there are predictions that the pharma industry will benefit from investment, as Croatia has been improving its healthcare system and pharmaceutical regulations to bring them into line with standards in the EU. German pharmaceutical distributor ANZAG reported that Croatia's pharmaceutical market grew by 4.3% during the second half of 2010 (3). In contrast, other emerging Eastern European markets didn't fare so well over the same period. Lithuania's pharma market, for example, decreased by 1.2% (3). As a whole, the pharmaceutical market of Central and Eastern Europe is growing at an annual rate of 7.7% (4), which puts the Croatian pharmaceutical market's positive growth rate in a favourable light. 

Better access to high quality healthcare is leading to a rise in demand for the latest medicines in Croatia. As a result of healthcare reforms, the Croatian Institute for Health Insurance (HZZO) has established a special budget to provide access to innovative medicines. Between July 2009 and July 2010, 47 innovative molecules were added to the HZZO's lists of reimbursed medicines (5, 6). The pricing system in Croatia is considered strict, with international price comparisons being used to set maximum wholesale prices. The HZZO evaluates drug prices in Italy, France and Slovenia, but if prices from these countries are not available, then data from Spain and the Czech Republic are considered instead. If a drug is thought to be a breakthrough product, then the system does allow a company to charge up to 100% of the average price in Italy, France and Slovenia. The HZZO insists that its decisions regarding product innovation take into account the importance of a medicinal product from a public health viewpoint, as well as therapeutic criteria. Therefore, at least according to the regulations, there are opportunities for branded medicines' manufacturers to profit from marketing expensive, innovative products in Croatia. 

As an industry, Croatia's pharmaceutical sector is very well developed. The pharmaceutical industry represents 4% of the country's total manufacturing industry and accounts for 1.7% of the manufacturing workforce. The major domestic pharmaceutical companies are Pliva, Belupo and Jadran Galenski Laboratorij (7), but around 50 international companies are also represented in the market, with more likely to enter now that EU entry has been confirmed. Croatia's adoption of better intellectual property laws, which are in line with EU standards, should also encourage other companies to enter the market. 

Croatia's pharmaceutical potential is best highlighted by Pliva, the country's leading company. More than 80% of Pliva's products are exported, with the US being one of its top foreign markets— exports to the US were valued at €62.8 million in 2010 (8). In May 2011, the company received an award from the Croatian government for becoming the country's leading exporter to the US. The company also was responsible for the discovery of the globally successful antibiotic azithromycin, which is registered under the brand name Sumamed. Pfizer marketed the drug internationally as Zithromax and this arrangement boosted Pliva's finances dramatically. When the US patent for Zithromax expired in 2005, however, Pliva was placed under tremendous pressure to maintain growth and it became a target for acquisition. In 2009, Pliva was integrated into Teva, which was interested in turning the company's Zagreb site into an R&D hub. 

One of the stumbling blocks to Croatia's EU application had been corruption and organised crime, and these issues continue to receive attention from those wary of Croatia's entry into the EU.  

At the end of 2010, for instance, Pliva was surprisingly mentioned as part of the wikileaks controversy concerning a previous takeover battle between Barr Pharmaceuticals (US) and Iceland-based Actavis. According to the media reports, there had been rumours that the Croatian Prime Minister, Ivo Sanader, had been in collusion with the chairman of Pliva to ensure that the company was sold to a US firm (11). To make matters more complicated, the US Ambassador was also quoted in the Croatian media as stating that the sale of Pliva to Barr Pharmaceuticals would represent a demonstration of confidence by US companies in Croatia's investment climate. According to information cited by wikileaks, Sanader was upset by the negative way in which the deal was being portrayed by some sections of the media and called the US Ambassador to issue a statement denying any improper action on his part. The US ambassador duly issued a statement to indicate that market forces alone would decide the outcome for Pliva, but privately, the cables indicate that the US embassy saw the sale as a challenge to Croatia's regulatory system. At the time of the takeover attempt, the share price of Pliva had risen by 60%, which gave the press considerable material for speculation regarding the real factors behind the deal making. Barr's initial €1.58billion offer for Pliva had been countered by a €1.72 billion from Actavis (9). According to the US Embassy's discussions with Barr, the US company was satisfied with the activities of the Croatian authorities in the matter. Pliva transferred ownership of its US business to Barr Pharmaceuticals in 2007. 

Another problem for Croatia is counterfeiting—even more so than for existing EU member states. The Croatian Customs Administration seized almost 1.3 million counterfeit items (10) in 2011, but despite these successes, the authorities say that the country is still being flooded with counterfeit products. These counterfeiting incidents have also affected the pharmaceutical sector. In 2010, a widely cited report appeared in a Croatian journal: out of 26 samples of erectile dysfunction drugs seized from an illegal supply chain, around half may have been counterfeit (11). To date, however, there have been no recorded incidents of counterfeit medicines entering the official supply chain. It is also worth putting incidents of counterfeits into perspective. In 2009, Pfizer conducted a study of pharmaceutical products seized by authorities under suspicion of being counterfeit Viagra. Of the total number of seizures worldwide, only approximately 1% came from Croatia— a similar level to many existing EU countries (12). 

As the EU expands, one major concern is securing the pharmaceutical supply chain. The new EU's pharmaceutical package highlights the fight against counterfeit medicines as a priority to protect patients and will probably lead to amendments to strengthen Directive 2001/83/EC and to Commission Directive 2003/94/EC, which relate to medicinal products for human use and good manufacturing practice, respectively. The EMA is working closely with the Croatian authorities to both improve the detection of counterfeits and suppress the activities of those behind the illegal trade. The subject was covered in a pre-accession meeting in June 2011, held in Zagreb (Croatia), involving the EMA and Croatia's national regulatory Agency for Medicinal Products and Medical Devices of Croatia (HALMED).  

The concerns about Croatia seem to have been overcome as the country's entry into the EU is on course for 2013. Because of its business environment and pricing system, Croatia is a challenging market, but it also offers a highly developed pharmaceutical sector and good growth prospects for the future. The fact that many international pharma companies have already moved into the market suggests that the industry is optimistic about its potential. 

1. BBC News, "Croatia cleared for EU membership in 2013" (UK, 2011). 

Croatia Pharmaceuticals and Healthcare Report Q3

3. ANZAG, "ANZAG: Result under pressure" press release (Germany, 2011) 

The Outlook for Pharmaceuticals in Central & Eastern Europe

6. L. Voncina "Croatian 2009–2010 pharma reform", Ekonom:east Media Group, online (Serbia, 2011), 

7. FarmaVita.Net, "Croatia — Pharmaceuticals and Biotechnology" (2011), 

, "US embassy cables: Allegations over Croatian pharmaceutical company deal rebutted" (UK, 2010) 

10. PETO EVIC, "Croatia Fights Counterfeiting" (Belgium, 2011). 

11. Securing Pharma, "Croatian study uncovers counterfeit medicines" (2010) 

12. V. Stecher et al., 12th Congress of the European Society for Sexual Medicine (Lyon, France, 2009). 

Croatia is on track to join the EU in 2013 and offers a well-developed pharmaceutical market. However, its EU membership application has undergone much scrutiny.