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As a part of Europe, but not the European Union, trials in Croatia can encounter special challenges
What does it mean to be European but not yet in the Union while conducting clinical research projects? Central and Eastern European (CEE) countries are well known to commercial sponsors of clinical trials, but which countries are included in this umbrella term can vary. Many business maps of Europe would include the following countries within the CEE region: Albania, Bosnia, Bulgaria, Croatia, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Serbia, and Slovakia—those countries formerly behind the Iron Curtain. However, many of these countries are now either new members of the EU or preparing for entry within the foreseeable future.
The CEE region has been involved in international clinical research for some years. Indeed, during the last decade, the CEE region has consistently proven to be a good place to do clinical research both in terms of quality and enrollment.1 This success demonstrates that being European but not an EU member is not an obstacle to producing high-quality clinical research and meeting enrollment targets.
Presently, both existing EU member states and those waiting patiently at its gates are busy adapting to the changes recent EU directives on clinical trials have brought to the arena of clinical research. Croatia, one of the countries approaching these gates, has already negotiated many of the choppy waters involved in implementing EU trial standards into local regulations. Consequently, its rates of enrollment remain good compared with larger European Union countries, and good levels of quality continue.
As a country, Croatia provides a natural conduit between EU and non-EU countries, with the added advantage that the Croatian language is easily understood by the non-EU countries that surround it. Therefore, it is not surprising that during the last decade many CROs have chosen Croatia as their starting point for opening offices in the southern reaches of the CEE area. Clearly, its population of 5 million is small compared to others in the CEE region. But the combination of language commonality coupled with its joint administrative heritage and infrastructure (born out of its days as Yugoslavia), means that Croatia offers a good starting point for business.
Both commercial and noncommercial sponsors of clinical trials are bound by the regulations contained within the EU directives 2001/EC/20 and 2005/EC/28. As a result, all interventional trials now need to comply with a single set of regulatory standards. This is a significant change for noncommercial interventional trials and is providing challenges throughout Europe. However, it does provide an increased benefit for centers to conduct commercial trials since they will learn the tact and background needed to meet these demanding standards.
A sizeable portion of Croatia's population—1.5 million—are concentrated in the vicinity of its Capital city, Zagreb. The centerpiece of the capital's health system is the University Hospital. This network is well supported throughout Croatia by a network of both regional and city hospitals, including three medical schools. Data on enrollment in clinical trials is not publicly available, but our experience has been that 47% of centers are located in Zagreb and these have achieved 74% of subjects enrolled. This suggests that there is potential for more research sites, which could be based around Croatia's three other major conurbations: Split, Rijeka, and Osijek (see Table 1).
Table 1. The number of clinical trial sites and number of subjects recruited per the largest university hospitals in the country.
As mentioned, the conduct of clinical trials provides valuable research experience for medical centers, but it also gives patients with a range of illnesses the opportunity to try new treatments. However, such research must be done within the framework of Good Clinical Practice to ensure that patients' rights and well-being remain at the fore at all times. For a small country, Croatia has a rich heritage in terms of science, including two Nobel prize winners, and more recently the development of azithromycin by Pliva, which was subsequently licensed to Pfizer. It is therefore no stranger to the demands and challenges of research.
Split, on the Adriatic coast, is Croatia's second largest city. Including the surrounding areas of the Dalmatian county, of which it is the capital, there are approximately 460,000 people. In terms of clinical trials, our experience has been that 13% of Croatian sites come from Split and these have contributed 7% of subjects enrolled. Like Zagreb, Split has its own medical faculty within its University. Some 300 kilometers to the north of Split, but also on the Adriatic coast, lies Rijeka, Croatia's third largest city. It too has a medical faculty within its University and has 300,000 inhabitants. Surprisingly, our experience with clinical trials enrollment has been relatively low in this location. Thus far, Rijeka has provided us with 11% of our Croatian sites but only yielded 4% of recruited subjects.
Croatia's fourth Medical University is located in the city of Osijek in the Eastern part of the country. Including the surrounding areas, it has a potential patient population of 330,000. Thus far, we have selected several sites in this location but the enrollment levels look low when compared to Zagreb's. However, a different picture emerges when we look at studies where sites are confined to Zagreb plus at least one other big city (see Table 2).
Table 2. The number of trial sites and subjects recruited for studies where sites were confined to Zagreb plus at least one big city.
Irrespective of which data we look at in relation to enrollment, what separates Croatia from other countries is that it usually reaches its peak recruitment quickly, using less sites than its neighbors in CEE countries. Moreover, timely enrollment is unquestionably a critical factor in the success of both commercial and noncommercial trials.2
Apart from a few small deviations, Croatian legislation has already incorporated EU directives. This initially created a few hiccups since Laws on Drugs and Medicinal Devices and the Guidelines on Clinical Trials and GCP gave firm directions to sponsors but then failed to provide the mechanisms to enable all parties to follow them. However, these initial challenges were largely resolved by September 2004, when first trials were approved by a Central Ethics Committee (CEC). This proved cathartic, since up until then an administrative backlog had developed somewhere between the demands shown in Laws and the operational realities of clinical trials.
However, there was more than a sense of déjà vu in 2007 when we again faced new regulations. But our early experience had made us better prepared for meeting the operational challenges which resulted from the introduction of legislation that has produced a stricter approach to site selection and still closer scrutiny of study contracts.
The process of trial approval in Croatia is now firmly established as a sequential one. The CEC is the first body that reviews a trial. It is required to give its opinion within 30 to 90 days (depending on the study phase and/or type of investigational product) from submission of all requested documentation. Following the approval by the CEC, the Ministry of Health then reviews the documentation and issues the approval using the same timeline. Experience thus far suggests that 60 days is usually sufficient to obtain approval from both of these bodies, provided the applications satisfy the criteria laid out.
Croatia, although European, is not yet an EU member. Therefore, investigational medicinal products (IMPs) cannot be delivered directly to study sites. Croatian legislation requires that an import license is obtained for both IMPs and laboratory kits. An import license takes 15 working days from the date of submission to obtain and is usually granted in the form of an annual license. Clearing all the necessary regulatory hurdles provides a timeline for initiation of three to four months after conducting site selection visits.
Access to well-educated, multilingual staff with established relationships with leading clinicians are key factors when placing either CRO offices or studies.3 The country's capital in Zagreb has already proven to be a successful center for clinical research in the commercial sector. Moreover, based on studies conducted by Altiora, there is evidence to suggest that there is still considerable potential in terms of study centers that can recruit well and to a high standard in three other locations: Split, Rijeka, and Osijek.
The inevitable by-product of conducting commercial trials is that these University Medical Centers will learn and adopt the modus operandi that is now required for all interventional studies irrespective of sponsors and thus attract more noncommercial, international work.
Sponsors looking for reliable start-up times and timely enrollment would do well to consider Croatia. This small country offers both the medical expertise and geographic concentration of population to ensure both. Like many of its European cousins already in the EU, Croatia also has considerable medical expertise and a proven track record in the conduct of clinical trials to the exacting standards of GCP. But unlike them, it continues to enroll patients in a timely fashion, thus making it an ever more attractive location for the conduct of clinical trials.
Josip Aralica, MD, is managing director of Altiora, Seferova 8, 10 000 Zagreb, Croatia, email: email@example.com
1. J. Demeter, "Selecting Sites and Investigators—An Approach for Central and Eastern Europe," Applied Clinical Trials, March 2002, 56-66.
2. A.M. McDonald, R.C. Knight, M.K. Campbell et al., What Influences Recruitment to Randomised Controlled Trials? A Review of Trials Funded by two UK Funding Agencies, Trials, 7 (9) 2006, http://www.trialsjournal.com/content/7/1/9.
3. W. Schaub, Strategies for Placing CRO Offices in Europe, Applied Clinical Trials, June 2002, 85-88.