Clinical Trials in the Baltic States

The term Baltic States typically refers to three north-central European counties located on the eastern edge of the Baltic Sea-Lithuania, Latvia, and Estonia (from south to north). Together these countries represent a population of 6.57 million in 2012.^{1, 2, 3} The Baltic States regained independence in 1990-1991 and began to emerge as an attractive clinical research market. Entering the European Union in 2004, the states harmonized their legislation with international clinical trial law and established a friendly environment for clinical trials. This again contributed a significant breakthrough to the clinical research in Baltic States. During the last decade the region authorized an average of 80 new clinical trial applications per country, per year and still has a potential for growth.

Population

There are nine cities in the Baltic States with a population exceeding 100,000 people and approximately 68% of the Baltic population is considered as urban. By the end of 2011 the titular nationalities of Lithuania, Latvia, and Estonia accounted 83.9%, 62.1% and 69.0%, respectively, of each country's population. Russians are by far the largest ethnic minority in the Baltics, accounting 26.9% of Latvian population and 25.5% of Estonia's. Russians in Lithuania account a relatively small etching group of 5.4%. Other notifiable ethnic groups include Poles, Belarusians, and Ukrainians, together accounting 7.3% of the Baltic population.^{1, 2, 3}

The Baltic States have a significant incidence of oncological and cardiovascular diseases. The environmental burden of these diseases is also above the average world rate given by the World Health Organization.^{4, 5} The region has one of the highest cardiovascular mortality rates in the European Union-the situation is worse in Bulgaria and Romania.⁶ Furthermore, similar to most of the Central and Eastern European countries the Baltics States can offer a considerably large pool of treatment-naïve subjects.

Of all the medicines consumed by Lithuanians, Latvians, and Estonians in 2010, 40.9% were cardiovascular drugs. Other notifiable anatomical therapeutic chemical groups include: alimentary tract and metabolism (13.8%), nervous system (11.3%), blood and blood forming organs (8.3%), musculoskeletal (8.1%), and respiratory (7.1%) systems.^{4, 5}

One of the dominant motives for a patient to participate in a clinical trial is a physician's recommendation. In the Baltics physician/patient relations are characterized by a high level of patient's trust and respect for the physician. A study conducted at the Lithuanian University of Health Sciences evaluated patients' opinions on clinical trials. The study revealed that over 90.7% of respondents trusted in their physicians and that trust significantly increased the possibility of a patient participating in a clinical trial in the future.⁷

Research sites and investigators

According to national health statistics, by the end of 2010 there were 285 hospitals and around 5,500 outpatient clinics (dentistry institutions not included) operating in the region. The private healthcare sector is well-developed: around 20% of hospitals and 90% of outpatient clinics are privately owned.^{1, 8, 9} As a rule, healthcare units concentrated in the bigger cities are well-equipped and can perform CT, MRI examinations, etc. There is also a vast number of laboratories, both state owned and private, offering high quality tests. However, currently no GLP certified laboratories are available in Lithuania and Estonia, and there is only one GLP certified laboratory in Latvia.

Currently there are around 23,000 physicians and 45,000 nursing staff practicing in the Baltic States.⁵ Baltic doctors are characterized as highly qualified professionals. The older generation speaks fluent Russian and has a medium level knowledge of the English language, while most of the younger physicians speak fluent English. Baltic physicians are motivated to work and do the job well. Besides the financial reasons, they see clinical trials as an opportunity to improve their qualifications, as well as to provide patients with free modern treatment and diagnostics.

While performing feasibility, it is important to make sure that the investigators have valid GCP training certificates. GCP trainings in Lithuania are regulated by the law (Good Clinical Practice Trainings Law, No. 1A-91, Jan 18, 2007). The law requires investigators to attend basic eight-hour GCP training and refresh their knowledge in four-hour courses every five years. There are no strict requirements for GCP certificates in Latvia and Estonia, however, they are required.

GCP trainings are well organized in the Baltics and most of the investigators are GCP trained. Since 2007, CRO Biomapas is certified by the State Medicines Control Agency to provide GCP trainings in Lithuania. In Latvia, GCP trainings are organized by an organization called Medicine Information Centre. There are no such organizations operating in Estonia, however bigger medical institutions tend to invite lecturers from the State Agency of Medicines of Estonia and organize GCP trainings for their employees participating in clinical trials in some medical institutions twice per year.

Statistics/structure of trials

The peak of new clinical trial applications in the Baltics was observed in 2008 (Figure 1). Similar to the rest of the world, due to the global economic crisis, Baltic States faced a decline in clinical trial application dynamics.^{10, 11, 12}

Currently the market is rather stagnated, though it shows some signs of recovery.

The majority of clinical studies performed in the region are Phase III trials. During 2012, Phase III studies accounted nearly 64% of all the applications submitted in the Baltics. Phase II studies had a share of 26% and Phase IV accounted for 4%. In 2012 there were 13 applications submitted to initiate Phase I trials in the Baltics.^{10, 11, 12}

Historically, oncology was by far the mostly researched area in the Baltics, however neurology/psychiatry took first place in 2012 with an average of 11 new applications registered (Figure 2). Similar to previous years, Lithuania had the highest number of applications in endocrinology in 2012. Therapeutic areas of oncology and pulmonology/allergy were more significantly researched in Latvia, while the country had a small share of applications in neurology/psychiatry if compared with Lithuania and Estonia. Furthermore, it should be noted that Estonia leads the way in infectious diseases and rheumatology, with 16 and 15 applications registered respectively in 2012.^{10, 11, 12}

Legislation

Following the European Union accession, the Baltic States have implemented EU directives 2001/20 and 2005/28, and incorporated GCP guidelines into the national law. Clinical trials are regulated by the national laws, regulations and orders, the fundamental ones include:

• Order of the Ministry of Health of Lithuania No V-435, May 31, 2006, "Regarding Confirmation of the Description of the Order on Approval to Conduct Clinical Trial of Medicinal Product, Issuance of Certificates and Permissions to Conduct Clinical Trial of Medicinal Product, Order of Performance, and Control of Trials."

• Law of the Republic of Lithuania No VIII-1679, May 11, 2000, "On Ethics of Biomedical Research."

• Regulation No. 23 of the Minister of Social Affairs of Estonia, February 17, 2005, "Conditions and Procedure for Conducting Clinical Trials of Medicinal Products."

• Cabinet Regulation No 289 of Latvia, March 23, 2010, "Regulations on Conducting Clinical Trials and Non-Interventional Studies and Labelling of Investigational Medicinal Products, and Procedure for Conducting Inspections on Compliance with the Requirements of Good Clinical Practice."

Most of regulatory documents are translated to English and available on the websites of national competent authorities and ethics committees.^{10, 11, 12, 13, 14}

Regulatory process

The competent authorities governing clinical trials in the Baltics are State Medicines Control Agency of Lithuania, State Agency of Medicines of Latvia, and State Agency of Medicines of Estonia. Competent authorities of Lithuania and Latvia authorize applications in a term not exceeding 60 days, whereas in Estonia Phase II-IV trials are authorized during a 30-day period, and Phase I during a 60-day period.

There are some nuances with the ethical review of clinical trials in each state. The Lithuanian Bioethics Committee (LBEC) is the main institution responsible for the ethical review of clinical trials in Lithuania. Additionally there are two regional biomedical research ethics committees in Lithuania: one in the Kaunas region (established in the Lithuanian University of Health Sciences), and one in the Vilnius region (established in the Medical faculty of Vilnius University). Regional committees have the authority to review applications for clinical studies planed only for research sites falling within the committee activity regions. Hence, applications for multicenter studies that cover both regions are subjected for LBEC review, which has the authority to issue a single opinion for the whole country. Both LBEC and regional committees review applications in a term not exceeding 60 days.

Two independent ethics committees are operating in Estonia: one in Tallinn (Tallinn Medical Research Ethics Committee), and one in Tartu (Ethics Review Committee on Human Research of the University of Tartu). A single opinion is required and, similar to Lithuania, the ethical review process takes not longer than 60 days.

There are four independent ethics committees in Latvia and a single opinion is required. All four committees conduct expertise in a term not exceeding 30 days, however their fees are not fixed and vary.

It is important to be aware that, in addition to the competent authority and the ethics committee, in order to proceed with a study in Lithuania an approval from the State Data Protection Inspectorate (SDPI) must be obtained. SDPI will approve the study only if the ethics committee and competent authority decisions are favorable. SDPI expertise should not exceed a period of 60 days.

The applications may be submitted in parallel to all the institutions. However, in order to speed up the process it should be done in an appropriate sequence, having in mind that the competent authorities issue the approval only after a favorable opinion of ethics committee is in place; SDIP will issue the approval only after favorable opinions from competent authority and ethics committee are in place. Based on experience, if the documentation is complete, in good quality, and is submitted depending on the institution meeting schedules, all the necessary approvals can be received in approximately 60 days.

Logistics

There are no import/export license requirements for clinical trial related materials-investigational medicinal products (IMP), laboratory kits, medical devices-within the Baltics and European Union. Also, no licenses are required for exports of biological samples to other EU countries. However, in Estonia an IMP import certificate must be obtained after the clinical trial is approved. In order to receive the certificate, a research site must submit an application for imports to the State Agency of Medicines of Estonia. The certificate is issued within five days after the application is received. These certificates are not to be presented at the customs and are designed mostly for IMP accountability purposes.

Sponsors should not face any problems with the distribution, since there is vast number of depots and courier companies, both international and local, operating in the Baltic region, offering storage and fast delivery of clinical trial materials to study sites.

Contracting and costs

There are no restrictions for clinical trial contracting in the Baltics. In practice, sponsors and/or contract research organizations usually sign two types of contracts-one with the institution and one directly with the investigator. The shares of payments are determined by the institutions. The payment size mainly depends on the rates adopted by the institution to cover the facility amortization and labor costs, which correlates with the complexity of the protocol procedures (patient examinations, physician and medical personnel time consumption, use of equipment, length of hospitalization, rate of return, etc.). The share of funds received by the institution typically ranges from 10% to 25% of the total clinical study budget per patient. It should be noted, that the instrumental and laboratory tests conducted in a medical institution have to be paid separately.

Summary/conclusions

The region has already proven its clinical research potential-the Baltic States approve around 80 new clinical trial applications per country each year. The biggest part of clinical trials performed in the Baltics fall within the therapeutic areas of oncology, neurology/psychiatry, and endocrinology; nearly 70% of the studies performed are Phase III trials.

States legislation is harmonized and the regulatory process is similar to other EU countries. The timelines are also attractive-the approval process takes approximately 60 days. The region has an appropriate population size, sufficient infrastructure, and experienced and motivated investigators. Considering these factors, as well as a history of steady growth in the past, the Baltic clinical research market is poised to grow.

Donatas Grina, is Business Development Manager, e-mail: donatas@biomapas.lt; Indre Tutlyte is Director of Business Development, e-mail: indre@biomapas.lt; and Audrius Sveikata, PhD, is Managing Director, audrius@biomapas.lt, all at CRO Biomapas, a CRO covering the Baltics, Belarus, and Russia.

References

1. Statistics Department of Lithuania, http://www.stat.gov.lt/en/.

2. Central Statistical Bureau of Latvia, http://www.csb.gov.lv/en/.

3. Statistics Estonia, http://www.stat.ee/.

4. "Health in the Baltic Countries 2010," 19th edition, (National Institute for Health Development of Estonia, Department of Health Statistics; The National Health Service of Latvia; Health Information Centre, Institute of Hygiene, Lithuania, 2011.), http://sic.hi.lt/html/en/hbc.htm.

5. World Health Organization, "Environmental Burden of Disease: Country Profiles," http://www.who.int/quantifying_ehimpacts/countryprofiles/en/.

6. R. Buivydas and G. Cerniauskas, "Financing of Healthcare System in Lithuania and Accessibility of Healthcare Services," Health Economics Centre, Vilnius (2011), http://www.sec.lt/lt/leidiniai/lietuvos-sveikatos-apsaugos-sistemos-finansavimas-ir-sveikatinimo-paslaug%C5%B3-prieinamumas.

7. V. Marciulioniene, "Evaluation of Clinical Trials from Patient Perspective", (2010), http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20100621_092519-20034 .

8. National Institute of Health Development of Estonia, http://www.tai.ee/.

9. The National Health Service of Latvia, http://vec.gov.lv/.

10. State Medicines Control Agency of Lithuania, http://www.vvkt.lt/.

11. State Agency of Medicines of Latvia. http://www.zva.gov.lv.

12. State Agency of Medicines of Estonia, http://www.sam.ee/.

13. Lithuanian Bioethics Committee, http://bioetika.sam.lt/.

14. Centre For Ethics of University of Tartu, http://www.eetikakeskus.ut.ee/.