Jcs western eastern europe

Market Report

Market Report

Western Eastern Europe – Another Region on a Global Map of International Clinical Trials The region of Central and Eastern Europe (CEE) entered international clinical trials (CT) about 20 years ago, and now it plays an important role in the clinical trial market, providing up to 9-10% of global enrolment.

The CEE region includes more than 20 post-communist countries and has a population of more than 340 million people. Eleven of these countries have already joined the European Union (EU).

At the same time the region is not homogeneous.

The countries are different not only in languages but also in living standards, access of their population to healthcare institutions, coverage of modern diagnostics and treatment, etc. Based on our 17-year experience in CT in the region we propose dividing CEE countries into three groups. These groups have similarities in terms of high patient and investigators’ motivation to participate in CT, but are different in terms of the possibility of enrolling different target populations.

One of these three groups is evidently and fairly quickly drifting towards the treatment and research standards of Western European countries, getting more and more capable of successfully contributing to trials which require modern technologies and highest diagnostic and treatment standards, and this allows us to define CT countries like the Czech Republic, Estonia, Hungary, Poland, Slovakia, and Slovenia as Western Eastern Europe.

CEE Region in Clinical Trials Following the fall of the Iron Curtain towards the end of the 1980s, CEE countries including post-Soviet states (altogether more than 20 countries) were exposed to a growing demand among pharmaceutical companies eager to conduct CTs. The CEE region’ population of 340 million citizens is comparable with the USA or Western Europe (WE) 1 .

The countries adopted ICH-GCP standards during the 1990s along with the USA and WE 2 . 11 CEE countries have joined the EU: Poland, the Czech Republic, Hungary, Bulgaria, Slovakia, Romania, Latvia, Lithuania, Estonia, and Slovenia (Croatia will finally become an EU member in 2013). Their membership made them integrate their legislation into the European legal framework, including the area covering clinical trials.

Gradually CEE countries have become a rather traditional place for CT. There are a number of reasons behind the growing demand for these countries. Most of them inherited centralised healthcare systems.

Historically, most have a limited number of specialised medical centres that enable substantial concentration of patients. The physicians and nurses in CEE countries 42 Journal for Clinical Studies

are well-educated 3 . Both community-owned and private clinics in these countries are able to enroll whenever needed not only pretreated but also treatment-naïve subjects, while WE in many cases provides the same “recycled” pool of patients who often are already rather treatment-resistant 2 . The existing vertical referral system in these countries provides only minimal competition (if any) for patients among medical centres.

Available access to life-long medical records of patients enables lower rates of screening failures and premature withdrawals 1,2 .

Figure 1: Availability of patient population

Further on, the region generally has a growing population migration rate but it is still much lower compared with WE, which enables better long-term follow-up 4 . Finally, it is important to point out that average site productivity in the region is often twice as high as in WE and the USA 2 . A further interesting feature of the region is the fact that, contrary to other regions, clinical research professionals frequently have medical or pharmaceutical education 5 .

Most of these countries already own up-to-date diagnostic and treatment facilities, including fusion imaging machines, genetic diagnostics and modern electronic data collection means. Usually CEE countries deal with Phase II and III CTs, in which the region provides a large pool of patients. The most represented areas of CT are oncology, cardiology, rheumatology, hypertension and neurology 6 . It is important to stress that the necessity to translate study documents for submission into local languages should be noted.

En masse clinical research professionals in the whole CEE region are either medical doctors, or pharmacists, or hold scientific degrees, which is perceived as a highly desired merit, enabling better and more efficient understanding of the study assumptions and methodology.

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Market Report The quality of work and data was a topic of numerous discussions, as well as abundant research compilations.

To confront the subject, it is important to underline that in general more than half of the inspections by FDAs in these countries did not require any follow-up action. All the inspections carried out in this region came up with fewer issues of compliance with protocol and data storage compared with inspections of the US and WE sites 1 . Also, fewer problems have been observed regarding informed consent forms and study procedures, inadequate drug accountability and failure to report adverse drug reactions compared to occurrences registered during inspections in WE and the USA. This region displays the lowest rate of inspections that require official or voluntary action 7 . The current experience of PSI includes 47 successful FDA and EMA site inspections just in the CEE region, as well as 11 inspections by CEE local regulatory agencies. We therefore consider that the conclusion of the data quality in CEE is being endorsed by our own rather extensive experience in this area.

The number of IND CTs registered in individual countries (source www.clinicaltrials.gov) shows an evident rise in the absolute number of CTs in all CEE countries between 2005 and 2011. The trend is stable over the last six years and constitutes an average growth of 31%.

Nevertheless, in comparison with the other “emerging” regions (e.g. Latin America, Asia), the growth is not that high any more. Clearly we are witnessing a renewal of the new emerging markets, first and foremost on Asia Pacific and Latin America having the share of the US and WE pretty stable.

The distribution of CTs of different phases in CEE is also pretty stable. The growth is witnessed only in the number of Phase I studies (from 19 newly registered in CEE Phase I studies in 2005 to 79 in 2011). The steepest increase in the number of Phase I CT in the CEE region is seen primarily in the Czech Republic (from one to 10), Poland (from five to 13), Hungary (from two to 14), Bulgaria (from zero to nine) and Russia (from six to 12). Our experience in performing more than 30 Phase I trials in the CEE region also indicates the high quality of the data and the growing interest of the sponsors in performing Phase I trials here.

Classification of CEE countries for CT We offer the following distribution of CEE countries: •

•

The 1st group of countries consists of Poland, the Czech Republic, Hungary, Slovakia, Slovenia and Estonia. They have already undergone a massive transformation of their social systems and from that standpoint they are to some extent comparable with WE countries. Treatment and diagnostic standards are distinct within the group, which make them very attractive in placing trials requiring patients pre-treated with modern medication and the most advanced diagnostic facilities.

The 2nd group – Russia, Bulgaria, Romania, Lithuania, Latvia, Croatia and Serbia – are the countries that have begun healthcare system reforms but still experience serious restrictions in healthcare funding, and access of their population to modern medical technologies and medicines is

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•

limited. These countries successfully contribute to most clinical trials but every time we should carefully evaluate the enrolment potential of their clinics to avoid overestimation of their capabilities.

The 3rd group of countries – Ukraine, Moldova, Bosnia and Herzegovina, Belarus, Armenia and Georgia – can be characterised as at the moment somewhat less economically developed states with low investment into the healthcare system. The availability of modern equipment (diagnostics, imaging and laboratory) is often limited, as well as the treatment options. However, even these countries demonstrate a gradual increase in healthcare spending, which enjoys a steadily growing popularity and a hefty motivation among investigators. It also has a high number of treatment-naïve patients. These countries carry the potential of achieving high enrolment rates for trials in such patient populations.

The presence of some infectious diseases to a certain degree can indicate the level of healthcare advancement, although primarily it is a factor in some CTs, e.g. TBC occurrence in trials of biological drugs, or infections such as hepatitis and HIV leading to patient exclusions.

Fortunately in the 1st group of countries (aka Western Eastern Europe) the level of these socially important infections is rather comparable to WE countries, and being in the focus of their healthcare systems.

Table 2: Basic medical indicators

Population, Economics Table 1 summarises some basic economic and population indicators. The data corresponds to our breakdown of CEE countries into three groups. The first group of CEE countries consists of rather developed countries with higher life expectancy.

Table 1: Economic and population indicators

* - all ages per 100,000 Source: http://www.euro.who.int/en/where-we-work

Source: http://www.euro.who.int/en/where-we-work , https://www.cia.gov/ library/publications/the-world-factbook/rankorder/2004rank.html

Medical Background When analysing the number of hospital beds per 100,000 inhabitants, it is obvious that some of the countries – primarily those belonging to the low-income group – have an obvious deficit of hospital beds. The opposite extreme is when hospital bed capacity is artificially inflated, which is evident for example in Russia, Ukraine and Belarus. The number of medical doctors per 100,000 inhabitants is surprisingly even throughout the region, with few exceptions.

Table 2 presents the standardised death rate (SDR) per 100,000 inhabitants in malignant neoplasms. These numbers are high in the CEE region, especially in the 1st group of countries, and this fact makes the region even more attractive for oncology studies.

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Regulatory, Start-up Comprehensive legislation on CTs is available in all countries of CEE. The regulatory process and submission vary from country to country and should be dealt with individually for each trial on the local level, but follow internationally accepted practices and GCP rules.

Some variation in the procedures of regulatory and ethics review itself does not pose a problem given the availability of local experts in charge of the start-up phase.

Based on our own experience of more than 300 CTs in the region, the system of getting a study authorisation works well. At the same time, delays may happen due to requests for additional documentation placed by authorities.

The approval process in CEE region and particularly in the group of “Western Eastern Europe” takes three to four months, and this is on average on a par with the WE region.

The second group of countries is far more diverse in that aspect. Approval in the Baltic countries is pretty fast. On the contrary, the process takes much longer in Croatia and Serbia and can be up to five to six months. Russia and Ukraine are usually somewhere in between in terms of the time needed to initiate a CT. The third group of countries occupies the medium position when it comes to start-up duration. Above all, Georgia stands out in terms of speed. Our experience also confirms that their regulatory bodies there are fast and effective. www.jforcs.com

Our Experience in Some “Western Eastern European” Countries - Focus on Poland, Czech Republic and Hungary As a company we have been running a lot of clinical trials in all countries of “Western Eastern Europe”, but for the sake of analyses we decided to concentrate on three countries where we have the greatest experience, trying to avoid bare advertisement by focusing in on a fair evaluation of pros and cons.

These three countries share fairly high and growing standards of treatment and diagnostics achieved with implementation of the most advanced methods. Thanks to the availability of modern treatment, diagnosis and laboratory facilities, pretreated in the standard population of patients, these countries are suitable for placing even the most complicated CTs. PSI recommends treating these countries as an option for placing Phase I studies as well as complex and complicated CTs, which are traditionally being run in the USA and WE only.

Poland Poland, with a population of 40 million citizens, has become a traditional destination for CTs, especially in oncology, hematology, cardiology, hemodialysis and transplantology. The expensive modern treatment is usually covered within the National Therapeutic Programs. Unfortunately, currently not all patients who require, for example, the treatment with new biologic agents, may have access to it due to limited funds dedicated to specialised treatment. However, the number of patients who have access to the most modern cures is growing from year to year.

Modern imaging facilities are also available in Poland.

Imaging facilities in Poland possess approximately 500 computer tomography machines and more than 170 MRI machines, as well as 10 PET/CT centres.

Poland, in many trials we ran, was among the countries with the highest number of patients enrolled and can still boast, in most cases, fast and efficient recruitment. An example of this is a Phase I/II study in Primary Immune Thrombocytopenia, where Poland not only enrolled patients effectively but also managed to enroll the first patient in this trial. Polish pharmaceutical law is rather friendly towards Phase I CTs, which can be conducted in different Polish research centres such as hospitals, private healthcare centres, and nine wellorganised Phase I units, which attracts pharmaceutical and biotech companies.

Participation in CT in some cases is the only alternative, or an opportunity for many oncology and hematology patients where very expensive treatment options are being tested. This significantly impacts patients’ participation in the studies, increasing the overall number of enrolled subjects.

We are currently conducting 55 studies in Poland and among them CTs in hematology (in particular in hemophilia), oncology, and in other indications such as pediatric medicine, nephrology, neurology (particularly multiple sclerosis), infectious disease in bacterial and viral infections etc.

It is important to note that since recently the submission dossier must include signed contracts with all sites, and currently each hospital has its own procedure for how Journal for Clinical Studies 45

Market Report to negotiate the study contract in clinical trials. There is no uniform country-level policy regarding this. All this may extend the overall start-up timelines and should be considered by a sponsor.

The Czech Republic The Czech Republic (CzR) with a population of 10.5 million people has caught up with Poland very fast, and currently is being looked upon for CT just like Germany or other similar countries, being one of the most welloff countries in the region. It has a sophisticated public insurance system with an average financial participation of patient´s rate at about 17% of all costs. Most medicines are fully or partially reimbursed from the public health insurance while the availability of modern treatment is generally unlimited.

It is commonly known that heart diseases are a leading cause of hospitalisation and mortality in Europe. There is a considerable variation across European countries in the use of coronary angioplasty, and the CzR holds the 4 th place in EU with its rate of coronary angioplasties per 100,000 inhabitants. Similarly, the rate of hip replacement surgeries in the CzR is above the EU average. Besides cardiology, another advanced field of CzR healthcare is transplantology. There are seven organ transplant centres in the republic, boasting a long credit history here.

The advantage of the CzR is a far advanced centralisation of healthcare resources into large and complex centres, which coordinate regional centres, or otherwise all patients with particular pathology are being referred to a few specialised institutions. For example, all kinds of biological treatment are tied to certified centres allocated for individual indications, such as rheumatoid arthritis, psoriasis, non-specific intestine inflammations, etc. Such systems, where patient care is centralised, the patients are databased and their availability for CTs is higher while the number of involved centres remains low, provides a huge advantage for CTs. The tail side of the coin is processes of “saturation” of the specialised sites in some indications, and thorough assessment of the capabilities of each site in each particular trial is crucially important.

Likewise, oncology care is organised in a similar arrangement with a network of 13 comprehensive cancer centres treating adults, two child treatment centres, and six hematology-oncology centres. These centres cover and coordinate treatment of all malignancies in the country. An online registry of diseases and patients (www.linkos.cz) is not merely unique by itself but is also a sole source of epidemiological data and treatment success rates.

Medical facilities throughout the CzR generally meet the highest standards. Such imaging procedures as computer tomography and MRIs are routine in all hospitals. There are also seven PET/CT centres. The latest development in this field is the opening of the Positron Treatment Center in Prague, which is only the fifth such facility in the whole of Europe, and the first in the CEE and non-EU region.

As of today, we are running 32 clinical trials in the CzR, including three Phase I studies. As often was the case, investigators in CzR showed high enrolment rates and expected patient recruitment targets have never been missed.

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Market Report Hungary Hungary is an attractive destination for clinical trials.

Over 300 clinical trials are being conducted in Hungary annually, which is an outstanding number, considering its population of below 10 million citizens. A wide range of modern treatments is available here. Biologics are available in specialised certified centres in different therapeutic indications. The number of such centres varies between nine and 20, depending on the indication.

There are 24 hematology departments, of which six are major centres in Hungary. The number of oncology departments is 30, out of which 5 major oncology centres must be pointed out. According to the statistics, Hungary holds the 8th place in the number of primary IPC procedures in Europe.

Short set-up and start-up timelines and its enrolment capabilities make the country very attractive for sponsors. Together with preparation for submission, EC/RA review and contract negotiations, start-up takes three months. Due to the fast site initiation after study approval, Hungary reached FPI in numerous clinical trials in which Hungary was involved. We are currently running 31 clinical trials in Hungary in numerous therapeutic areas. In not less than half of them, FPI milestones were achieved on time or even ahead of schedule.

Phase I clinical trials can be conducted at treatment centres holding a Phase I certification of the National Institute of Pharmacy. All centres must apply for the certification every three years. There are 14 Phase I certified treatment centres in Hungary, and out of these 11 centres are Phase I certified clinical or hospital departments covering a certain therapeutic area. There is only one pediatric department with Phase I certification specialising in pediatric oncology. The centre was, for example, a top enroller in a pediatric Phase I trial conducted in children with Ewing’s family of tumours or rhabdomyosarcoma.

The high qualification of clinical trial monitoring staff makes the country very attractive for CROs and sponsors. Most clinical research employees are either medical doctors or pharmacists or hold a scientific degree.

Conclusion and Summary Pharmaceutical research and development far outpace the market. This is important since pharmaceutical companies continuously channel 10-20% of revenues to research and development (9). While expenditures grow, the initial costs remain practically unchanged, which compels pharmaceutical companies to look for practical solutions to this situation.

The CEE region is one of the optimal options due to rapid enrolment, high quality of data, motivation and loyalty of investigators, low dropout rate, reasonable costs, and educated clinical research professionals.

Among all CEE countries, we distinguish a group of “Western Eastern European Countries” that have been implementing treatment standards and diagnostics technologies close to the countries of WE. Countries of Western Eastern Europe enable treatment and data quality while cutting clinical trial expenses compared to WE or the USA. Poland, the Czech Republic, Hungary, Estonia, Slovakia and Slovenia can be attributed to the group without any doubt.

In general the group of “Western Eastern European countries” enables complicated clinical trials to take place under conditions broadly similar to those in the USA or WE. References 1. Caldron PH, Gavrilova SI, Kropf S. Why (not) go east? Comparison of

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findings from FDA Investigational New Drug study site inspections performed in Central and Eastern Europe with results from the USA, Western Europe, and other parts of the world: Drug Des Devel Ther.

2012; 6: 53–60.

Tassignon JP, Sinackievich N. Speeding the critical path. Appl Clin Trials. 2004;13(1):42-48.

Smith-Marshall P. Recruitment strategies: A European perspective.

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Ben-Am M, Gemperli B., Covelli A, Burke G. The pharmaceutical industry and oncology in Central and Eastern Europe. Ann Oncol.

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Platonov PG. Clinical trials in Ruassia and Eastern Europe: recruitment and quality. Int J Clin Pharmacol Ther. 2003;41(7):277-280.

Virk KP, Clinical Trials in Central and Eastern Europe: The Challenge of Dealing with Multiple Languages and Cultures, The Monitor ACRP, October 2008, http://www.languageconnections.com/ descargas/CLINICAL%20TRIALS%20IN%20CENTRAL%20&%20 EASTERN%20EUROPE.pdf

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7. Platonov PG, Varshavsky S. FDA inspections outside the USA: an Eastern European perspective. Appl Clin Trials. 2004;13(9):60-66.

8. http://www.accessdata.fda.gov/scripts/inspsearch/ 9. Kreger JC. Session 117, CRO Market Snapshot: Analaysts´Perspective.

DIA 38th Annual Meeting, Chicago, July 2002

Tomas Novak, PharmD, Manager Feasibility Research and Patient Recruitment Services at PSI CRO AG, is a graduate of Pharmaceutical Faculty, Charles University Prague. Before joining PSI in 2011, he had worked for 4 years for other CRO as a feasibility and site identification specialist within a start-up group. He also has many years of practical clinical pharmacy experience from an emergency pharmacy attached to a major university hospital in Prague where he both dealt with retail sales of prescription medication, patient counseling and supervised the production of cancer treatment infusions at a state-ofthe-art clinical drug preparation laboratory.

Email: tomas.novak@psi-cro.com

Katarzyna Moscicka, MSc Pharmacy is a Director Feasibility Research and Patient Recruitment Services at PSI CRO AG. Before joining PSI in 2008, she worked at the Angiogenesis and Anti-angiogenesis Research Group, Department of Cell Biology, Maria Sklodowska-Curie Oncology Center-Institute, Poland and her main research focus was on an angiogenic gene therapy.

Katarzyna is a co-author of one publication.

Email: katarzyna.moscicka@psi-cro.com

Veronika Fekete, MD is a Senior Clinical Trial Specialist at PSI CRO AG. Before joining PSI in 2011, she had worked at the Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Hungary for 4 years. Her main research focus was on cardiovascular stress adaptation in pathological conditions.

To date Veronika is the co-author of 4 publications.

Email: veronika.fekete@psi-cro.com

Maxim Belotserkovsky, MD, PhD, MBA is the Head of Medical Affairs at PSI CRO AG. He is a board-certified physician in Internal Medicine, Rheumatology, Anesthesiology and Intensive Care, Nephrology and Hemodialysis, an Associate Professor of Pathological Physiology and a Member of Russian Academy of Natural Science. He has more than 15 years of experience in clinical research as an investigator and clinical research professional.

He is also the author/co-author of more than 100 publications.

Email: maxim.belotserkovsky@psi-cro.com Journal for Clinical Studies 47