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Trials are on the rise in the country, where recruitment rates are high but custom procedures can pose a problem.
As the established market for clinical trials becomes increasingly competitive in the United States and Western Europe, relatively new regions are becoming a popular location for clinical researchers. Health care systems, experienced investigators, a large population, cultural closeness to Western Europe, and comparatively lower costs make Eastern European countries attractive to pharmaceutical companies and global CROs.
It is clear that the business climate in Eastern Europe has changed dramatically during the past decade. Many Eastern European countries, including several former Soviet republics, have entered into the European Union and are now perceived as equals to Western European countries—some of their neighbors have not entered the EU yet.
The most important countries for clinical research from the first group are Poland and the Czech Republic. The clinical trials market is large there, and for many companies these two countries are part of the obligatory checklist for new study locations. According to CenterWatch,1 in 2006 there were 29.7 clinical trials per million people in the Czech Republic and 8.7 per million in Poland.
From the second group (the non-EU Eastern European countries), Ukraine is worth everybody's attention. This country is a relative newcomer to the industry, but should be considered a potential country for clinical research development.
Using Ukraine's geographic coordinates, the geographic center of Europe is located on Ukraine's territory, located near the Rahiv, Lviv region. The country borders Poland, Belarus, Russia, Moldova, and Hungary, and with an estimated population of more than 46 million2 is first among the Central and Eastern European countries, except Russia (see Table 1)2,3.
Table 1. Population figures for Eastern Europe.
Medical and pharmaceutical sciences are widespread. There are 15 medical universities and academies, four medical faculties of classic universities, three academies of postgraduate medical education, and 33 scientific medical institutes. There are also many pharmaceutical companies located in Ukraine that meet GMP standards, and 18,000 drugs (with 3411 active pharmaceutical ingredients) registered in the country.4
The unique features of the Ukrainian medical care system help recruit patients for trials within a short time frame. Primary and specialist care is organized around large hospitals and covers a large population. The system has a centralized structure and vertical referral system, which means that principal investigators (who are at the top of the referral pyramid) can select patients from the regional population without any competition inside.
Often patients come from small cities to big centers for detailed diagnosis and treatment, which is advantageous for trials as well. Overall, more than 65% of inhabitants live in urban areas;2 in other words, clinical trials have easy access to more than 30 million Ukrainians. There are 30.16 doctors per 10,000 inhabitants—whereas, there are 22.43 in Poland, 34.03 in France, 34.02 in Germany, and 13.92 in Turkey.5
There is no nationwide insurance system for health-related expense reimbursement in Ukraine. People need to pay out of their own pockets for treatment, and high-quality medications are rather expensive. Free of charge treatment guaranteed by the country's constitution and provided by most governmental hospitals is limited, uses generic drugs, and is often not up-to-date. Although there are some governmental and/or pharmaceutical company funded programs for certain types of diseases (e.g., cancer, HIV, tuberculosis, and cystic fibrosis), they do not cover the needs of the whole population.
A study often provides a much better standard of care for a patient than the national health services, since it incorporates not only study medication but a full set of health care services including free lab testing, instrumental diagnostics, deep medical observation, and in-patient care. For many people, the trial may be the only way to get modern diagnostic procedures and potentially effective treatment. This is likely to make potential Ukrainian patients motivated to enter a trial, and keeps them constantly compliant to the study protocol.
Another relevant feature of Ukraine's medical care system: poor efficacy of routine screening and prophylaxis activities. As a consequence, the rate of untreated or late-stage diseases is very high, which may make Ukraine attractive for projects with slow recruitment in Western European countries. Studies in late-stage oncology diseases, untreated hypertension, and L-Dopa naïve Parkinson disease have the potential to recruit the necessary number of patients on time in Ukraine. According to Ukrainian official statistics, there are approximately 32,000 new cases of different diseases per year.2
According to some authors,6 today the research-based pharmaceutical industry taps less than 15% of the clinical trials enrollment potential of the Russia/Ukraine/Balkans region. (Since the actual number of trials currently conducted in Ukraine is much lower than in other countries, that percentage is smaller for Ukraine and thus even more impressive.) The number of clinical trials in the country significantly increased during the past 10 years with development of modern legislation and gains in popularity. According to statistics,7 only six international clinical trials were conducted in the country in 1996. Nine years later, in 2005, there were 125 trials. In spite of such growth, the potential capacity is still huge.
When comparing Ukraine's capabilities with key criteria used by sponsors during country selection for multinational trials8 (see Table 2), the Ukraine scores well in more than half of the criteria. Reasons for the good scores include: a lot of sites and investigators have conducted clinical trials and have extensive ICH-GCP training; the majority of principal investigators are professors or chiefs of departments and are very experienced in the field of medicine they specialize in; there is a Central Ethics Committee, which acts as an ICH-GCP compliant entity; and there are a number of possibilities for subject recruitment. In addition, most potential sites have good Internet access (or it can be established easily), and have experienced PC users on staff. Thus, there should not be any substantial problems using electronic data capture systems or conducting trials with modern approaches/methods.
Table 2. Key criteria used by sponsors when selecting countries for multinational trials.
There are some difficulties when conducting clinical trials in Ukraine, but they are surmountable. One of the main concerns is import/ export issues. Special permission from Regulatory Authorities is necessary for any study-related import/export activity. Custom procedures, both import and export, could take several days, and this should be considered when developing time frames for drug or biological sample shipments. International courier companies operating in Ukraine provide a full set of services, including ambient and frozen sample shipments and temperature controlled shipments of investigational products. It should be taken into consideration that even excellent courier companies have to deal with custom procedures. For example, it could take several days to clear a batch of thermo-controlled boxes through customs. In other words, courier service is not bad, but it is not as flexible as in Western Europe.
The other difficulty is language. Many study documents must be translated, not only because it is required by Regulatory authorities but also to increase understanding by investigators who may not be fluent in English. There are two main languages in the Ukraine: Ukrainian and Russian. As patient-oriented information should be delivered in the native language, it is necessary to have informed consent documents, patient diaries, and booklets both in Ukrainian and Russian.
The laboratory can also be a source of unexpected difficulty. Laboratories in most of the municipal hospitals are not able to provide full coagulation, biochemistry or immunology panels. To have consistent laboratory data, one possible solution is to use one laboratory for all study sites. Although opinions differ, such a central Ukrainian lab may be a good option for clinical trials with many sites. In general, a local CRO could be the best way for pharmaceutical companies to get closer to people in Ukraine and achieve project success.
The State Pharmacological Center of the Ministry of Health of Ukraine governs clinical trials in the country. This entity is also responsible for drug registration, inspections, pharmacovigilance, and other activities (see Figure 1).9 Legislation has been in place since 1996. Bridging the gap between the current system and procedures stipulated by the EU Clinical Trials Directive is now accomplished. The law "About Medicinal Products" (1996) and Order #66 of the Ukrainian Ministry of Health (which incorporates the fundamental points of directive 2001/20/EU) are the main documents that regulate clinical trials in the country.
Figure 1. Organizational Chart of the State harmacological Center of the Ministry of Health of Ukraine.
To initiate a clinical trial in Ukraine, the sponsor company should submit a package of documents to the State Pharmacological Center and the Central Ethics Committee of the Ministry of Health. There are local ethics committees in many hospitals/institutions, but usually the Central one is used to get approval for international multicenter trials. (Documents to be submitted are listed in Table 3.10 ) The Center's officer will conclude whether all documents are present in the package and whether they fulfill all general requirements. An officer has 10 days to provide their conclusions in writing.
Table 3. List of main documents to be submitted for clinical trial conduct in the Ukraine.
When issued a positive primary conclusion, the State Pharmacological Center has 60 days to familiarize itself with the clinical trial materials, to discuss them, and to request further information from the applicant or provide a final conclusion. As a rule, the Center's clinical trials board has a monthly sitting (at the end of each month, except in August). Documents to the Ethics Committee can be submitted in parallel with the State Pharmacological Center. The Central Ethics Committee has sittings at the end of each month too. It can take several days after the sitting to issue written approval documents.
A rough flow chart (see Figure 2) illustrates the main steps of the regulatory process. State Pharmacological Center rates for expert evaluation of clinical trial materials are approximately f1800 EUR (11,900 UAH) if the investigational product is registered in the manufacturing country and approximately f2900 EUR (19,480 UAH) if the investigational product is not registered in the manufacturing country. Evaluation of any subsequent amendments costs approximately f325 EUR (2180 UAH). The Central Ethics Committee evaluates clinical trial materials free of charge.
Figure 2. A flow chart illustrating the main steps of the regulatory process for clinical trial approval in the Ukraine.
To receive import permission (for drugs, laboratory kits, and any additional equipment) and export permission (for lab samples) the package of documents should be submitted to the State Pharmacological Center. It could take up to three weeks to obtain permissions. Upon completion of the trial, a final report should be submitted to the regulatory authority.
Since 1999, the State Pharmacological Center has conducted regular inspections of investigational sites, pharmaceutical companies, and CROs. In total, 272 inspections have been conducted by Center inspectors—27 of them were inspections of international clinical trials.11
Several insurance companies propose policies for clinical trial subjects. Their rates are slightly different, but the main feature is a rather small index: insurance rate/insurance compensation. It is important to note that only licensed companies, residents of Ukraine, can insure citizens. Malpractice insurance and insurance for investigators is not obligatory in Ukraine. Sponsors should also take into consideration that poststudy insurance coverage is not required in Ukraine; thus, it is not incorporated into the typical insurance agreement. This latter item should be discussed separately.
Clinical Trials: Ukraine's Strengths
Many factors contribute to the continual increase in the number of clinical trials being placed in the Ukraine. More and more big pharmaceutical companies and global CROs are discovering that Ukraine is a country with great potential for clinical research. Among the most prominent features of Ukraine is high average site productivity and long-standing readiness of the local population to try new and improved medication.
In addition to the principal investigators and other site staff being highly qualified, they have been able to gain significant clinical research experience over the past decade. Authorities made a lot of effort and succeeded in providing modern and ICH-GCP compliant legislation, ensuring the quality of approved investigational sites, and training many investigators on ICH-GCP and national regulations.
There is a large selection of local CROs or representatives of global ones, and they can guide sponsors in overcoming all difficulties and help them to complete even the most difficult projects in Ukraine on time and with excellent data quality.
Olena Rudnyeva, MD, is a project manager at SPRI Clinical Trials, 37-41, Artema str, Kyiv, Ukraine, email: firstname.lastname@example.org
1. C. Veryyard, Report about Applied Clinical Trials 13th Annual European Summit in 2006.
3. The World Factbook, https://www.cia.gov/cia/publications/factbook/index.html.
4. V.T. Chumak and O.P. Baula, "Pharmaceutical development—One of the main parts of ensuring quality of medicinal products," Materials of the first Ukrainian Clinical Trials conference on medicinal products in Ukraine (Kyiv 2006).
6. N. Sinackevich and J.P. Tassingnon, "Speeding the Critical Path," Applied Clinical Trials, January 2004, 42–48.
7. V.I. Maltsev and V.G. Lyzogub, "Clinical Trials in Ukraine," Materials of the first Ukrainian Clinical Trials conference on medicinal products in Ukraine (Kyiv 2006).
8. Thompson BioWorld, Clinical Trials State of the Industry Report 2005, p 71.
10. Order #66 of the Ukrainian Ministry of Health, February 13, 2006.
11. L.I. Kovtun and S.I. Rasputnyak, "Clinical Trial inspections in Ukraine," Materials of the first Ukrainian Clinical Trials conference on medicinal products in Ukraine (Kyiv 2006).