The region is not homogeneous. These 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, and more. Based on our 17-year experience in CT in the region, we propose allocating CEE countries into three groups. These groups have similarities in terms of high patient and investigator motivation to participate in CT, but are different in terms of the possibility to enroll various target populations. One of these three groups is moving pretty quickly 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. We will define these countries — like Czech Republic, Estonia, Hungary, Poland, Slovakia, and Slovenia — as Western Eastern Europe.
CEE for Clinical Trials
Following the fall of the Iron Curtain towards the end of 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, as mentioned, has the population of 340 million citizens, comparable with the U.S. or Western Europe (WE).1
The countries adopted ICH-GCP standards during the ’90s along with the U.S. and WE.2 Eleven CEE countries have joined EU: Poland, Czech Republic, Hungary, Bulgaria, Slovakia, Romania, Latvia, Lithuania, Estonia, and Slovenia (Croatia will become 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 centralized healthcare systems. Historically, most have a limited number of specialized medical centers, enabling substantial concentration of patients. The physicians and nurses in CEE countries tend to be well-educated.3 Both community-owned and private clinics in these countries are able to enroll 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 centers. Available access to life-long medical records of patients enables lower rates of screening failures and premature withdrawals.1,2
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 higher than in WE and U.S.2 A further interesting feature of the region is the fact that, contrary to other regions, clinical research professionals tend to have medical or pharma 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, reumatology, hypertension and neurology.6 Important to stress the necessity to translate study documents for submission into local languages.
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.
The quality of work and data has been 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 FDA’s inspections 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 compare with inspections to the U.S. and WE sites.1 Also, fewer problems have been observed regarding Informed Consent Form and study procedures, inadequate drug accountability and failure to report adverse drug reactions compared to occurrences registered during inspections in WE and U.S. This region displays the lowest rate of inspections that require official or voluntary action.7 Our current experience includes 47 successful FDA and EMA site inspections in the CEE region, as well as 11 inspections of CEE Local Regulatory Agencies. Due to that we 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, per www.clinicaltrials.gov, shows a 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 so high. Clearly we are witnessing a renewal of the new emerging markets, first and foremost on Asia Pacific and Latin America, with the share in the U.S. and WE pretty stable.
The distribution of CTs of different phases in CEE is also stable. Growth was 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 CEE region is seen primarily in the Czech Republic (from 1 to 10), Poland (from 5 to 13), Hungary (from 2 to 14), Bulgaria (from 0 to 9) and Russia (from 6 to 12). Our experience in performing more than 30 Phase I trials in the CEE region also indicates high quality of the data and the growing interest of the sponsors to perform Phase I trials here.
Classification of CEE countries for CT
We offer the following distribution of CEE countries:
- The first 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 second 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; access of their population to modern medical technologies and medicines is limited. These countries successfully contribute to most clinical trials but one should carefully evaluate the enrollment potential of their clinics to avoid overestimation of their capabilities.
- The third group of countries — Ukraine, Moldova, Bosnia and Herzegovina, Belarus, Armenia, and Georgia — can be characterized as at the moment somewhat less economically developed states with low investment in their healthcare systems. The availability of modern equipment (diagnostics, imaging, and laboratory) is often limited, as are treatment options. However, even these countries demonstrate a gradual increase in the healthcare spending, which enjoys a steadily growing popularity and a hefty motivation among investigators. This group also has a high number of treatment-naïve patients. These countries carry a potential of achieving high enrollment rates for trials in such patient population.
Table 1 summarizes 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 more developed countries with higher life expectancies.
When analyzing 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 standardized death rate (SDR) per 100,000 inhabitants in malignant neoplasms. These numbers are high in the CEE region, especially in the first group of countries, a fact that makes the region even more attractive for oncology studies.
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 lead to patient exclusions. Fortunately in the first group of countries (a.k.a. Western Eastern Europe) the level of these socially important infections is rather comparable to WE countries and is the focus of their healthcare systems.
Comprehensive legislation on CTs is available in all countries of CEE. The regulatory process and submissions 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 authorization 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 “Western Eastern Europe” group, takes three to four months and this is on a par with the WE region.
The second group of countries is far more diverse in that aspect. The approval in the Baltic countries is pretty fast. On the contrary, the process takes much longer in Croatia and Serbia and can be as long as five or 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 regulatory bodies there are fast and effective.
As a company we have been running a lot of clinical trials in all countries of the “Western Eastern Europe,” but for the sake of analyses we decided to concentrate on three countries where we have the biggest experience, focusing on a fair evaluation of pros and cons.
These three countries share pretty high and growing standards of treatment and diagnostics, achieved by implementing 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 the placing even the most complicated CTs. We recommend treating these countries as an option for placing Phase I studies as well as complex and complicated CTs, which are traditionally being run only in the U.S. and WE.
Poland, with a population of 40 million, has become a traditional destination for CTs and 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 treatment with new biologic agents, for example, may have access to them due to limited funds dedicated to specialized 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 centers.
In many trials we ran, Poland was among the countries with the highest number of patients enrolled and can still boast, in most cases, fast and efficient recruitment. In a Phase I/II study in Primary Immune Thrombocytopenia, Poland not just 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 centers such as hospitals, private healthcare centers as well as nine well-organized Phase I units, which attracts pharma 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 currently conduct 55 studies in Poland, covering hematology (in particular in hemophilia), oncology, pediatric medicine, nephrology, neurology (particularly multiple sclerosis), and infectious disease in bacterial and viral infections. It is important to note that, since recently, the submission dossier must include signed contracts with all sites and each hospital currently has its own procedure how to negotiate the study contract for clinical trials. There is no uniform country-level policy regarding this. All this may extend the overall startup timelines and should be considered by a sponsor.
The Czech Republic
The Czech Republic (CzR) with the 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 countries, being one of the most well-off 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.
Heart disease is a leading cause of hospitalization and mortality in Europe. There is considerable variation across European countries in the use of coronary angioplasty and the CzR holds the fourth place in the 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. Beside cardiology, another advanced field of the CzR healthcare is transplantology. There are seven organ transplant centers in the republic, boasting pretty long credit history here.
The advantage of the CzR is a far advanced centralization of healthcare resources into large and complex centers, which coordinate regional centers, or otherwise all patients with particular pathology are referred to few specialized institutions. For example, all kinds of biological treatment are tied to certified centers allocated for individual indications, such as rheumatoid arthritis, psoriasis, non-specific intestine inflammations, etc. Such systems — where patient care is centralized, the patients are databased and their availability for CTs is higher while the number of involved centers remains low — provide a huge advantage for CTs.
The flipside of the coin is the “saturation” of specialized sites in some indications; thorough assessment of the capabilities of each site in each particular trial is crucial.
Likewise, oncology care is organized in a similar arrangement with a network of 13 Comprehensive Cancer Centers treating adults, two child treatment centers and six hematology-oncology centers. These centers cover and coordinate treatment of all malignancies in the country. An online CzR registry of diseases and patients (www.linkos.cz) is not merely unique 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 a routine in all hospitals. There are also seven PET/CT centers. The latest development in this field is the opening of the Positron Treatment Center in Prague, which is only the fifth such facility in all of Europe and the first in CEE and non-EU region.
As of today, we run 32 clinical trials in the CzR including three Phase I studies. As often was the case, investigators in CzR showed high enrollment rates and expected patient recruitment targets have never been missed.
Hungary is an attractive destination for clinical trials. More than 300 clinical trials are being conducted in Hungary annually, which is an outstanding number, considering its population is below 10 million citizens. A wide range of modern treatments is available here. Biologics are available in specialized certified centers in different therapeutic indications. The number of such centers varies between nine and 20 depending on the indication.
There are 24 hematology departments, out of these six major centers in Hungary. The number of oncology departments is 30, out of these five major oncology centers must be pointed out. According to the statistics, Hungary holds the eighth place in the number of primary IPC procedures in Europe.
Short set-up and start-up timelines and its enrollment capabilities make the country very attractive for sponsors. Together with the preparation for submission, EC/RA review and contract negotiations the 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 running currently 31 clinical trials in Hungary in numerous therapeutic areas. In at least half of them, FPI milestones were achieved on time or even ahead of schedule.
Phase I clinical trials can be conducted at treatment centers holding a Phase I certification of the National Institute of Pharmacy. All centers must apply for the certification every three years. There are 14 Phase I certified treatment centers in Hungary, out of these 11 centers are Phase I certified clinical or hospital departments covering a certain therapeutic area. There is only one pediatric department with Phase I certification specialized for pediatric oncology. The center was a top enroller in a pediatric Phase I trial conducted in children with Ewing’s family of tumors 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.
Pharma R&D far outpaces this market. It is important since pharma companies continuously channel 10-20% of revenues to R&D.(9) While expenditures grow, initial costs remain practically unchanged, which compels pharma companies to look for practical solutions of this situation.
The CEE region is one of the optimal options due to rapid enrollment, 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 U.S. Poland, 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 under conditions very similar to those in the U.S. or WE.
- Caldron PH, Gavrilova SI, Kropf S. Why (not) go east? Comparison of 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. Appl Clin Trials. 2006;15(2):44-52.
- Ben-Am M, Gemperli B., Covelli A, Burke G. The pharmaceutical industry and oncology in Central and Eastern Europe. Ann Oncol. 1999;10 Suppl 6:15-17.
- 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
- Platonov PG, Varshavsky S. FDA inspections outside the USA: an Eastern European perspective. Appl Clin Trials. 2004;13(9):60-66.
- Kreger JC. Session 117, CRO Market Snapshot: Analaysts´Perspective. DIA 38th Annual Meeting, Chicago, July 2002
Maxim Belotserkovsky, M.D., Ph.D., is head of Medical Affairs at PSI CRO AG. Veronika Fekete, M.D., is senior Clinical Trial Specialist at PSI CRO AG. Katarzyna Moscicka, M.Sc. Pharmacy, is director Feasibility Research and Patient Recruitment Services at PSI CRO AG. Tomas Novak, Pharm.D., is manager Feasibility Research and Patient Recruitment Services at PSI CRO AG. For more information about this article, please contact Maxim.Belotserkovsky@psi-cro.com.