Clinical Trials in Serbia: From Strong to Stronger

For drug manufacturers intending to conduct clinical trials on a global scale, ascertaining the complex and at times ambiguous ethical and regulatory requirements of various countries can be a rather daunting experience. In Serbia, fortunately, this is not the case, as this country has consistently identified ways to further improve its already streamlined procedures for initiating clinical studies. There has never been a better time to conduct clinical research in Serbia, as the country has undeniably become one of the most popular destinations in this ever competitive field.

Good Clinical Practice (GCP)-compliant, multicenter clinical trials were common practice in the former Yugoslavia until the 1990s, when the nation descended into a bloody and futile civil war with the gradual formation of five separate republics. As these individual countries get ready for eventual EU membership, Serbia, more than any other ex-Yugoslav state, has radically reinvented and positioned itself as a leading center in Europe for high-quality, cost-efficient clinical studies.

A thriving industry

The pharmaceutical industry has been recognized for some time as a key factor in the Serbian economy, and the Belgrade government has been actively involved in stimulating growth in this valuable sector. At the same time, the department of trade and industry is at the forefront in promoting foreign investment and encouraging international companies to establish their businesses in Serbia.

This goal is steadily being achieved through the government's recent introduction of low-tax incentives, which together with the availability of an already well-established, educated, skilled, and cost-effective labor force at all levels, makes Serbia a most interesting investment opportunity. Indeed, the tax regime in Serbia is such that it has arguably become the envy of Europe,¹ with corporate profit tax (fixed at 10%) cited as one of the lowest in the continent to the point where it is now even more competitive than in Ireland (see Table 1).

Table 1. Corporate profit tax rates for 2004

The Serbian authorities have also implemented tax credits for investments in fixed assets, with an upper limit of 80% of the invested amount. In addition, venture capitalists can also benefit from a 10-year tax breather for investments over $7.5 million.

These steadfast efforts are already bearing fruit, as global giants such as GSK have made substantial gains in one of Serbia's leading pharma companies, Hemofarm Concern. Over the years, this Vrsac-based company along with its main market share competitor Galenika in Belgrade have made substantial investments in R&D, and as a result have expanded their product portfolio. Their pragmatic steps have ultimately paid dividends, making them even more attractive for further foreign financial input.

Another leading Serbian company that has recently benefited from these positive developments is Zdravlje in Leskovac. This manufacturer of generic products for gastroenterology and cardiology was acquired by the Icelandic company Actavis in 2002. In 2004, Actavis invested some $8.3 million and plans for a further investment of $24 million by 2008; it is also continuing to develop its sales presence in a number of neighboring countries and beyond. Zdravlje Actavis has close to 200 registered pharmaceutical preparations, and last year alone introduced 14 new products.

Clinical research

Serbia prides itself on having an impressive number of prestigious universities and medical schools along with well-established hospitals located in major cities and towns such as Belgrade, Novi Sad, Nis, Kragujevac, Kraljevo, Leskovac, Vrsac, Subotica, Zrenjanin, Sremska Mitrovica, and Pristina.

These institutions are adequately equipped with the latest scientific and medical instruments and have highly qualified, experienced staff. Furthermore, the vast majority of investigators from these institutes have extensive experience in leading clinical research strategies both at home and abroad, or at the very least, they have conducted trials as part of a global research program and are naturally fluent in English. Incidentally, Serbia has the highest percentage of English language speakers in southeastern and central Europe² (see Figure 1).

Figure 1. Familiarity with the English language.

Moreover, the country has gained an auspicious reputation for high rates of evaluable subject recruitment, with high patient compliance stemming in part from the confidence the Serbian general public has in the medical profession. This is especially evident in oncology, rare disease, and pediatric clinical trials, which have become increasingly difficult to conduct in Western countries because of considerable patient reluctance. This is not to say that high recruitment rates in Serbia are attributed to some degree of indifference or naivety on the part of the subject, but rather on their immense eagerness to learn and try novel treatments for their ailments.

Furthermore, the general public have always had a high interest in health matters, with health care issues occupying a dominant position in the media and in most cases gaining more public interest than general current affairs. One also should take into account the fact that Serbia & Montenegro is one of the largest populated countries in the surrounding region, with a populace approaching 11 million (see Figure 2).

Figure 2. Population of Serbia-Montenegro & surrounding countries.

Not surprisingly, in response to the high interest in conducting clinical trials in Serbia, more and more CROs have established offices in Belgrade. They have done so not only to meet the increasing demands for clinical studies in the country, but also to act as an ideal strategic center of operations for the Balkan region and neighboring territories. In fact, satisfaction within the pharmaceutical world with clinical research conducted in Serbia has resulted in the number of studies more than doubling over the past few years (see Table 2).

Table 2. Number of ongoing CTs in Serbia

Ethics committees

The current ethics committee (EC) procedure in Serbia is very straightforward. All key clinical research institutions across the country have their own local ethics committees (LECs) that meet on a monthly basis and comply with the ICH guidelines for GCP. Their operations and decisions are closely monitored and have a well-established reputation over the years for professionalism and efficiency. One major plus point for sponsors wishing to conduct a multicenter study is that only one LEC approval is necessary for all relevant sites.

The review process is quick, with protocols being approved within 30 days (although the approval process has been known to be as short as three weeks). A list of the key documents required for submission is outlined in Table 3. In keeping with the existing streamlined procedure, ethics submissions can be done in parallel with the regulatory application. However, it should be noted that the Serbian Regulatory Agency has to receive a copy of the EC approval before issuing their formal authorization.

Table 3. Some key documents required by Serbia´s Ethics Committees

In order to ensure the continued effective and efficient running of ECs, the establishment of a central ethics committee (CEC) at the Serbian Medical Association is being finalized this year.³ The working group will consist of a set number of members who will meet on a regular basis to oversee the review of Phase I clinical trial applications.⁴ The CEC will ultimately be responsible for monitoring the performance of LECs and will have the overall authority to ascertain whether a clinical trial is deemed suitable to proceed.

It is also anticipated that the CEC will play a pivotal educational role by making physicians aware of ethical dilemmas and by contributing to the training of research teams. Board members will be men and women from nursing, legal, and religious backgrounds as well as physicians and scientists.

Regulatory issues

Clinical trial applications are assessed and approved by the Medicines and Medical Devices Agency of Serbia (a division of the Ministry of Health), commonly referred to as ALIMS (Agencija za lekove i medicinska sredstva Srbije). The agency is responsible for instigating legislation and guidelines pertaining to medicinal products, medical devices, biologicals, food supplements, and cosmetics. ALIMS is also responsible for ensuring the safety and effectiveness of medicinal products, regulating controlled substances, and approving manufactured and imported medical devices.

With the government's implementation of revised clinical research legislation in 2004 (Official Gazette of the Republic of Serbia No. 84/2004), the aim of bridging the gap between the current system and procedures stipulated by the EU Clinical Trials Directive is now accomplished. Above all, the regulatory procedure for clinical trial application (CTA) approvals is wholly transparent, quicker, and even more efficient, with most studies approved well within the 60-day review period.

Additionally, members of staff at the agency have been known to be particularly helpful, with written queries regarding document requirements and other pertinent issues being promptly dealt with. The application form can be obtained from the agency's Web site (www.alims.sr.gov.yu) and the information to be filled in is very similar to that required in the EudraCT form. Table 4 gives a list of the key regulatory requirements stipulated in the CTA form.

Table 4. Essential documents required for regulatory submission as stipulated in the ALIMS application form

Once received and validated, the CTA dossier is subsequently reviewed by a panel of scientific experts who currently meet on the first Tuesday of every month to discuss and ultimately give their verdict on the application. Final regulatory approval is issued as soon as the agency receives a copy of the positive opinion from the EC.

Furthermore, the study drug import procedure is very clear cut—only three documents are requested by customs. Required is a copy of the regulatory approval letter, a declaration from the coordinating investigator regarding the purpose of the study medication, and the proforma invoice.

Once the clinical trial has ended, ALIMS requests a copy of the final report to be forwarded to them for the completion of the regulatory procedure.

Conclusions

Serbia has for some time now witnessed a continual increase in the number of commercial and noncommercial clinical studies conducted within its borders. The country's popularity among foreign sponsors has been attributed in part to government and health ministerial initiatives, where legislation pertaining to clinical trials is very much on par with that in the European Union. Other key contributing factors are the availability of highly qualified medical staff and the long-standing readiness of the local population to try new and improved medicines for the treatment of their conditions.

These practical approaches have ultimately placed Serbia in a highly competitive position in comparison to a number of EU member states that have yet to implement the Clinical Trials Directive and, notably, accession countries that are gradually losing their competitive edge in terms of subject availability and increasing study-related overheads. This upward trend is set to continue as the country prepares itself for imminent EU membership.

CTs in Serbia: A Case Study

After struggling to find sufficient patient numbers for a rare disease study in the European Union, the decision was made to recruit patients in Serbia. Here, the potential for high-quality clinical research had only recently been tapped by global pharmaceutical companies despite the relatively large population within this particular region of Europe.

Within three weeks, we had identified and conducted preselection visits at three possible sites in Belgrade, Novi Sad, and Nis. The hospitals at these centers were highly reputable, and the investigators were of high international standing within their therapeutic areas of research.

Serbian translations were naturally required for the patient information sheet, informed consent form, and study drug labels and regulatory authorization was obtained within 30 days. In a similar manner, the EC reviewed and approved the application within three weeks. Both applications were submitted in parallel, allowing us to begin work at the Serbian sites approximately six weeks after the feasibility study was completed.

The Investigators screened 18 patients within four weeks (an impressive number given the rarity of the condition), all of whom were successfully randomized. The overall level of enrollment at the Serbian sites ultimately contributed to the entire global recruitment process to such an extent that the total patient number target for the program was achieved well before the deadline date. Consequently, the sponsor did not need to proceed with a number of other countries that were on the reserve list.

Rory Gallagher, PhD, is a senior member of the regulatory affairs department, Chiltern International, 171 Bath Road, Slough, UK, SL1 4AA, +44 1753 216695, fax +44 1753 511116, email: rory.gallagher@chiltern.com

References

1. Pharmaceutical Industry in Serbia—Serbia Investment and Export Promotion Agency (SIEPA).

2. Investment Guide—Serbia, 2nd Edition, May 2005, Bank Austria Creditanstalt.

3. Development of Research Ethics in Serbia—Vladislav Stefanovic.

4. "Changing Clinical Trial Regulations for a Transforming Yugoslavia," Good Clinical Practice Journal, 9 (11).