Clinical Trials: Serbia
A Region Reborn
Jelena Barjaktarovic, Maxim Belotserkovsky, Mirjana Jovanovic and Melita Zonic at PSI CRO AG
Considering that an annual average of 1.5 million patients are enroled in studies globally in a number of indications, the leading sites of the western world are becoming increasingly saturated. This leads to the gradual decrease of the enrolment rate, the growing competition for patients among similar trials and the rising costs of conducting studies (1). This forces drug developers and clinical research organisations (CROs) to search for new and reliable locations for conducting quality clinical research. Nevertheless, the globalisation of clinical trials, which has been ongoing for the past two decades, is leading to the increase of other countries – Central and Eastern Europe (CEE), Asia, Africa and Latin America – participating in clinical trials (2). It is also a fact that approximately 10 per cent of clinical trials – and 12-13 per cent of patients – are enroled in clinical trials in CEE (2).
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At the same time, if we look at how clinical trials are distributed among the countries of CEE, we will see that approximately 2/3-3/4 of all studies in the region are placed in four countries: Czech Republic, Hungary, Poland and Russia (9). There are also a few small countries where the density of clinical trials is quite high, such as the Baltic States, which include Estonia, Latvia and Lithuania. There is another group of CEE countries wherein the number of clinical trials is steadily growing, for example Bulgaria, Croatia and Romania. At the same time, there are countries which have considerable potential for clinical trials, but are out of the focus of drug developers and CROs. One country that may contribute to clinical trial sites is Serbia. The Republic of Serbia is a country on the Balkan Peninsula with a population of 7.2 million people. The gross domestic product (GDP) per capita is about $10,500 per person, slightly below Bulgaria and Romania – two countries that are more widely represented in clinical trials.
Images: www.sxc.hu
Traditionally, around half of clinical trial patients are enroled in the US, with 20-25 per cent more being scouted in Western Europe. However, one country is emerging as an attractive place to host new sites: Serbia
Serbia has inherited, from former Yugoslavia, its healthcare system, which allows easy access to medical care for all. The healthcare system in Serbia is quite centralised and patients with different pathologies naturally gravitate to the limited number of specialised centres (21). The result is that these major hospitals, which are prospective centres for clinical trials, are usually adjacent to medical schools or medical research institutions, therefore they are capable of concentrating multiple patients with particular groups of diseases. So far, the funding of the healthcare system has mainly been done through the Republic Health Insurance Fund. Private healthcare takes a smaller share. On the whole, there are approximately 100 clinical centres in Serbia that have personnel and facilities required for participation in clinical trials. On top of this, there are five medical schools (including the recent US Medical School), which can actively participate in various clinical studies (6). The life expectancy in Serbia is relatively high and exceeds 74 years, with the leading causes of mortality being cardiovascular June 2013
conditions and malignancies. Considering that the demand for clinical trials in both of these therapeutic areas, especially in oncology, is huge, Serbia, unfortunately, has a significantly higher incidence of cervical, breast, and lung cancers than the European average (20). The shortage of funding of some modern medicines leads to patients wanting to participate in trials wherein they can obtain access to modern diagnostics and treatment methods. Additionally, as the overall wage is not that high in Serbia, this leads to a number of medical doctors working as clinical research professionals, and primarily clinical research associates (CRAs). On the other hand, this provides for a high quality level of medical monitoring and mindful site selection for each particular trial. In 2006, clinical trials were included by the Ministry of Healthcare on the list of leading opportunities of strategic importance for Serbia, promoting a very favourable attitude to clinical research on the official level (11). An important fact contributing to the promising clinical research climate is the possibility of having the study documentation and all communication with sponsors/ CROs in English (exc ept for the source records at the clinics). According to official data, 42 per cent of the Serbian population can speak English, which is significantly higher than in neighbouring countries. The majority of physicians also understand and speak English well.
sufficiently known as a provider of clinical trial data, while the countries that are better known, particularly the countries of the CEE that have joined the European Union, participate in a greater number of clinical trials. Another factor is that there is quite a long waiting period for Regulatory Authorities’ (RA) approval – again, in comparison with other CEE countries. In 2012, the number of overall clinical trials in neighbouring countries was as follows: ●● 439 in Croatia (4.5 million inhabitants) ●● 1,077 in Romania (22 million inhabitants) ●● 2,493 in Poland (40 million inhabitants) ●● 743 in Ukraine (45 million inhabitants) ●● 904 in Turkey (72 million inhabitants) ●● 260 in Slovenia (2 million inhabitants) ●● 1,532 in Hungary (10 million inhabitants) ●● 812 in Slovakia (5.5 million inhabitants) ●● 1,732 in Czech Republic (10 million inhabitants) ●● 1,103 in Greece (10.5 million inhabitants) ●● 362 in Serbia (7.2 million inhabitants) Our experience with cinical trials in Serbia by indication is summarised in Table 1. Typically, sites in Serbia have little time to enrol patients. The reason for that is two-fold: firstly, in a number of studies, it transpired that Serbia was the country of second choice as a rescue
country; and secondly, the estimated start-up period for a business in Serbia is relatively long (four to five months). Despite the limited enrolment period, investigators managed, in almost all cases, not only to achieve but also to exceed enrolment goals. This suggests that the time between site initiation and enrolment of a first patient is remarkably low, and from here on the enrolment picked up speed. A recent example of fast and effective enrolment was a study in end-stage renal disease patients with syndrome hyperphosphatemia on dialysis. Serbia was a ‘rescue country’ for this project and had only one and a half months for enrolment, which also occurred in the summer holiday season. In spite of this, eight Serbian sites managed to screen more than 110 patients and enrol 71 of them. In the end, it turned out that the Serbian sites were the most productive in the entire trial, even though the enrolment for the other countries lasted for more than 12 months. This success was achieved due to thorough pre-screening of patients, motivated teams and the availability of sufficient clinical staff members to quickly enrol patients. Multiple client audits, as well as two local regulatory inspections, have revealed the absence of serious quality concerns. Needless to say,
Table 1: Enrolment per study by PSI Serbia (completed trials)
It is important to note that the number of clinical trials in Serbia is not currently growing, but since 2006 approximately 90-110 new studies have been approved each year (19). However, regardless of all things factored in, such as the favourable attitude of the government, the medical community and patients’ willingness to participate in clinical trials, the number of trials is still stagnant. There is a need to discover the root of this problem, while taking the general growth trend of global trials into consideration. In our research, we have identified two main challenges that Serbia is faced with, which probably preclude the growth of the local clinical research market. The leading factor is that Serbia is not www.samedanltd.com
Indication Number Effective enrolment Enrolment rate of sites period (months) (patients per month)
Total enrolment (targeted number of patients/achieved number of patients)
Acute myeloid leukemia
5
12
0.83
10/10
Hepatitis B virus
4
3
12
25/36
Renal cell carcinoma
5
4
5
20/20
Non-small cell lung cancer
3
7
2.85
16/20
Breast cancer
4
5
2.4
16/12
Multiple myeloma
5
23/20
Hyperphosphatemia 8
1.5
47
34/71
Paediatric 2
10
2.7
11/27
Multiple sclerosis
12
5.2
15/62
Hyperphosphatemia 6
8
7.5
20/45
Hodgkin lymphoma
3
11
0.81
8/9
Haemophilia A
1
4
0.2
1/1
Colorectal Ca
6
8
5.9
20/47
3
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but after the sites are initiated, they will be very productive and will surely catch up.
Conclusion
for each country and for each study, a thorough feasibility assessment has to be performed. For example, patients who have received two or three lines of very expensive treatment would be quite difficult to enrol in Serbia, which is the same as in any other CEE country, due to local financial constrains. On the other hand, treatment-naïve patients in the same indication may be more easily accessible in Serbia than in other countries. Availability and accessibility of the required equipment should also be thoroughly assessed, in addition to logistic requirements. The second challenge for Serbia is related to the time it takes to receive an approval for clinical trials. On the whole, the study review process after the documents are received in-house takes four to five months. At the same time, we should note that the review process, even though time-consuming, is well-structured, well-organised and strictly regulated by legislation, and the attitude of the local authorities towards the clinical trials is positive. Furthermore, for the past year or two, efforts to shorten the regulatory timelines have intensified, with some positive trend. In the case of a small study with an indication where the enrolment rate is expected to rise steeply, such as hypertension, a client in all certainty would not want to wait too long for the approval. However, as far as major
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trials are concerned, where hundreds or thousands of patients have to be enroled, at sites that are likely to be heavily saturated with competitive trials (like multiple sclerosis or lung cancer) or where no one can expect speedy enrolment (such as platinumresistant ovarian cancer), Serbia can contribute significantly. It will not be the first country to start enroling,
It is evident that Serbia is quite an attractive place for clinical trials because of the combination of the established system of regulatory/ ethics review, and being a country that on the whole very positively embraces the idea of clinical trials. When making a decision to place a particular trial in Serbia, the usual length of regulatory review/study start-up timelines has to be taken into consideration, while on the other hand, it should be noted that the high productivity of Serbian sites will rather easily override the wait. References 1. Prüss Üstün A and Corvalán C, Preventing disease through healthy environments: towards an estimate of the environmental burden of disease, World Health Organization,
About the authors Jelena Barjaktarovic is a Senior Clinical Trial Specialist at PSI CRO AG. She is a graduate of the Medical School at University of Belgrade, Serbia. She started working as a Clinical Research Associate at PSI, and continued working in this position until 2011 when she joined the Medical Affairs Department. Jelena is currently studying for an MBA at the University of Sheffield. E-mail: jelena.barjaktarovic@psi-cro.com Maxim Belotserkovsky is the Head of Medical Affairs at PSI CRO AG. He has more than 20 years of experience in clinical research as an investigator and clinical research professional. He is also the author/co-author of more than 130 publications. E-mail: maxim.belotserkovsky@psi-cro.com Mirjana Jovanovic is the Country Manager at PSI CRO AG covering Serbia and the Balkan region since 2008. She is a board-certified Medical Doctor in both Serbia and US and has nine years of clinical research experience. Before working in clinical research, she worked at the Institute on Mental Health in Belgrade, Serbia. E-mail: mirjana. jovanovic@psi-cro.com Melita Zonic has been a Matrix Services officer at PSI CRO AG since 2010. She graduated from the Department of English Language and Literature, University of Belgrade. She has more than 15 years of experience in translating and editing, in addition to working as a medical interpreter in the US. She has also co-authored an EnglishSerbian dictionary. E-mail: melita.zonic@psi-cro.com
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