CLINICAL RESEARCH |
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Clinical research in Ukraine and Moldova
World Pharma News Network’s editor, Dr. Patricia Lobo visited the CRO, INNOPHAR Innovative Pharma Research Eastern Europe GmbH (IPR-EE) and its clinical sites in Ukraine and Moldova. There she met Dr. Karl M. Eckl and Dr. Franz Janik, Directors of INNOPHAR GmbH, the German parent company, and talked with them about their experience in conducting clinical research in Eastern Europe.
IPR-EE was among the first organisations to appreciate the excellent geopolitical conditions for conducting Phase I and Phase IIa clinical studies in Ukraine and Moldova and was successful in establishing good relationships with authorities in both countries.
Q. Tell me about IPR-EE’s history and how your CRO evolved.
 Dr Valery Brodan (anaesthetist & emergency therapist/site investigator ) is observing a volunteer on a stress test |
A. Innovative Pharma Research Eastern Europe (IPR-EE) is a CRO with two clinical sites, one in Boyan, Ukraine and one in Chisinau, Moldova. InnoPhaR GmbH is an organisation based in Germany that acts as the holding company for the two clinical sites in Eastern Europe. In both Ukraine and Moldova, they are officially listed as accredited clinical sites. The two sites are fully compliant with current GCP and ICH guidelines.
We began in the autumn of 2000 as a collaborative venture involving a German CRO, which started in Mönchengladbach, Germany in 2000, and the Bukovinian State Medical Academy in Chernivtsi, the capital of the District of Bukovina in the south west of Ukraine. Members of the Bukovinian State Medical Academy were very keen to combine their local academic experience to develop clinical research with the professional skills of a Western European CRO that worked to GCP standards.
Most major or global CROs conducting clinical research in Eastern Europe first established offices in Kiev, the capital of Ukraine, to gain access to the established Health Authorities and patient population in local hospitals. Meanwhile, in the Bukovinian District, there was a large, untapped patient population where clinical research could be conducted. Initially, IPR-EE operated as a clinical site at the Bukovinian State Medical University where we performed several clinical studies. However, in 2002, IPR-EE decided to expand – so we registered it as a private company in the Ukraine.
Q. How did you expand in Eastern Europe?
A. In 2004 we moved to a new facility in Boyan which is 12km south of Chernivtsi. This site is registered as a private hospital and has received official accreditation from the Ukraine Ministry, since the autumn of 2006, as a medical institution to perform clinical research activities. Collaboration with the Bukovinian State Medical University was officially ended in 2002, but we had built a good rapport with many of the academic members of major medical institutions in this state who now continue to work with IPR-EE. We see this as a mutual benefit.
Also, in 2004, we made contact with the Moldovian authorities to extend our clinical research activities to Moldova. IPR-EE was officially invited to start business in Moldova. Currently, Moldovian legislation does not allow private clinics to be established in Moldova. Accordingly, IPR-EE has collaborated with the National Institute of Cardiology for clinical studies whilst registering the company (InnoPhaR Innovative Pharma Research MO S.R.L.) in Moldova. IPR-EE operates its clinical research facility in Moldova on one floor of the National Institute of Cardiology building in the city of Chisinau, the capital of Moldova.
Q. What are the capabilities and capacity of IPR-EE’s Boyan-Ukraine site and Chisinau-Moldova site?
 Continuous cardiac monitoring is performed on a healthy volunteer |
A. IPR-EE has experience mainly in clinical pharmacology research in Phase I and Phase IIa (proof of concept) studies, but we also have experience and capabilities to carry out clinical trials in Phase IIb and Phase III studies. In total, IPR-EE currently has 36 beds, but has enough space to accommodate up to 60 beds. IPR-EE’s private clinical research unit in the Boyan-Ukraine site is equipped with a total of 18 beds in three wards (six beds per ward) and there is room for another 18 beds. At the Chisinau- Moldova site, IRP-EE can use 24 beds within the National Institute of Cardiology.
All rooms are equipped with the latest equipment for blood pressure/heart rate measurements, ECG recordings (QTc prolongation), telemetry, echocardiography, measurement of haematological parameters, Doppler-sonography of cranial vessels, rheoencephalography, echoencephalography, stress tests, lung function tests, urodynamics, prick tests, glucose stress test, and abdominal ultrasound imaging. Standard equipment and state-of-the-art standard operating procedures for intensive care are in place and study participants are permanently supervised through an emergency care specialist. We also have space for blood and tissue sampling and a laboratory for the determination of all relevant clinical- chemical parameters collected in the course of a study in the vicinity.
Q. What staff expertise do you have?
A. We are unique in that, unlike many CROs who have CRAs (Clinical Research Associates) with graduate or postgraduate degrees, IPREE’s specialist physicians are trained by us to carry out clinical research to GCP standards. In total we have 64 staff; 38 are full time staff and 26 work for IPR-EE on contract on a project-related basis, eg, medical experts to discuss specific medical queries, to recruit appropriate patients for specific therapeutic indication studies, or to supervise “their” patients in our clinical sites during the clinical conduct of a study.
Dr Janik and myself, Dr Eckl, are the Study Directors for studies conducted in Eastern Europe while Dr Nahum Tsvitbaum, who is our Deputy Executive and Medical Director, is an experienced anaesthetist and clinical pharmacologist who worked in leading positions in major hospitals in Chernivtsi for more than 20 years. The staff includes 21 physicians, 13 medical experts, 14 nurses, six project managers, seven QC and two external QA people. In both countries basic medical or scientific training is both to a high standard and practice oriented. Also the educational level of nurses is very high and in general confirmed by a certificate of an academic institution. In both countries recruited staff members are motivated to acquire experience in clinical research. Young physicians and scientists up to 35 years have a good command of the English language and in many cases also have been trained in Western European countries or the US.
 Clinical site (for Phase I/Phase IIA studies) of IPR-EE at Boyan, Ukraine |
There is either no or only rudimentary experience of the practical aspects of clinical trials and the practical implementation of GCP, or in European or US standards of study documentation. In these areas initial and ongoing training for at least two years is necessary. This could limit the dynamic growth of local CROs in these two countries. It is particularly difficult to convince young physicians to leave their working place in hospitals to work for a private medical institution as there is no long experience with private medicine in Ukraine or Moldova. Also, employees with good project management skills are difficult to recruit and intensive training is necessary for new staff.
Therefore we started to educate and train young and highly motivated individuals from various medical disciplines, eg nurses, physicians with different medical expertise, for the implementation of GCP and related regulatory requirements (such as the EC-Directive for clinical trials) according to the European and US standards. Such training is updated on a regular basis. In addition, we focus on the training requirements for the specific needs of the various study types we conduct, including strict adherence to protocol requirements, safety issues and precautions regarding the nature of the compound under research, the disease state of patients to be included in our studies, and medical emergency training.
Q. What about your experience in terms of clinical research studies?
A. Our two clinical pharmacology units specialise in performing Phase I and Phase IIa studies in healthy volunteers and as special focus, patient populations. We also carry out Phase IIb and Phase III studies in a number of therapeutic areas. We have access to special patient populations such as oncology (various indications), renal (kidney) diseases, urology, liver diseases, endocrinology, infectious diseases, dermatology, HIV patients and other areas such as gastroenterology, CNS, CVS and asthma/COPD. From these patient populations a significant number are naïve to latest therapies used in Western European countries.
Q. What is the system for recruiting healthy volunteers and patients in Eastern Europe?
A. Recruitment of healthy volunteers is usually initiated by press announcements in local newspapers or by word of mouth. We have also started advertising online via the Internet. Unlike most Western countries, countries in Eastern Europe have a central database of patients. In every major city there are large hospitals, known as Polyclinics, which offer different medical specialities or fields with departments under one roof, all belonging to a central organisation. All types of patients with whatever kind of diseases are seen in these Polyclinics on an annual basis.
IPR-EE has very good relationships with these Polyclinics for recruitment of all types of patient populations. Patients are recruited by medical experts in Polyclinics in the local vicinity, but in a decentralised manner. This recruitment process has the advantage of a rapid recruitment and high enrolment rate, with access to lots of patients in each therapeutic area, and a pre-study selection procedure to identify qualified patients, even during the regulatory approval process, to speed up and guarantee quick enrolment of patients for clinical studies. In Moldova, for example, all the major hospitals are located in the capital, Chisinau, while patients from all over the country go there for diagnosis and therapy purposes.
Q. What practical issues are there in establishing relations with the authorities in Ukraine?
A. As IPR-EE is located in Boyan, which is far away from Kiev, the capital of Ukraine, this geographical distance was the first problem we encountered along the pathway to becoming accepted by the Ukraine authorities based in Kiev. Some clinical studies could not be started because the authorities in Kiev had difficulty in understanding and being reassured that medical experience and safety of study participants could be guaranteed outside an academic institution. It is thanks to the reputation, credibility and expertise of Dr Nahum Tsvitbaum, who used all possible diplomacy and endless patience in establishing an open dialogue with the authorities in Kiev, which finally brought about IPR-EE full acceptance by the Ukraine Health Ministry, Central Ethics Committee and the State Pharmacology Centre. We have built on this relationship which has strengthened over the years. The State Pharmacology Centre supported the development of clinical research activities in Ukraine according to European standards substantially during the last few years. They also supported our clinical site in adoption of study documentation to local legal requirements.
Another practical issue we overcame was to shorten approval times for Phase I and Phase IIa clinical studies. Phase I clinical studies of development compounds by foreign pharmaceutical companies were only approved by established Health Authorities to be performed in medical institutions in Eastern Europe in the last 10 years. There was very little experience of medical institutions in Ukraine for Phase I and Phase IIa studies so it was difficult to provide support to these authorities with expert medical opinions, which would then cause delays in the approval process.
Usually, the approval process in the Western countries for a clinical study is achieved after two months and a competent authority has to respond within 60 days following the submission of documents. However, in the last few years, there has been greater understanding with the Kiev authorities of the necessity to gain experience in the field of Phase I and Phase IIa business. As IPR-EE is one of only a few medical institutions in Eastern Europe and currently the one with the most experience in performing Phase I and Phase IIa clinical studies according to European standards, a fruitful dialogue has started between IPR-EE and the Kiev authorities.
Since 2005, GCP and GMP standards have been implemented and accepted by Ukraine authorities and the local pharmaceutical industry. It was due to the Pharmacology Centre of the Ministry of Health of Ukraine that GCP standards were legalised by order no 373 on 22 July 2005. The whole approval process for clinical studies is based on European standards and the ethical principles operate at the same level as for Western Europe.
However, because of the different situation of study participants in relation to medical support and health insurance compared to Western Europe or US, new ethical issues may arise and will need to be considered. Therefore there is a need for a careful ethical approach for each new clinical study to be performed.
Q. What about Moldova, what was your experience with authorities there?
A. Right from our very first contact with the Moldavian authorities, there was great interest and enthusiasm shown by the authorities for IPR-EE, as a Western European CRO, to start clinical research in Moldova, even though Moldova did not have experience with Phase I and Phase IIa clinical studies, only some experience in the conduct of international multicentre Phase III clinical trials. As there are currently few clinical studies performed in Moldova, the approval process generally takes four weeks after submission of documents. Ethical issues and protocol design can be discussed beforehand with the Ethics Committee and the Drug Agency in a prescribed manner. Both legal bodies have highly experienced and well trained members from different medical and scientific disciplines. As in Ukraine, Moldovian authorities and the Ethics Committee seek to attain levels that are comparable with European standards and, therefore, contacts with different medical and scientific organisations in Western European and US institutions will help support and speed up the process of assimilation.
As in Ukraine, lack of experience in the practical aspects of Phase I and Phase IIa clinical studies may cause a delay in the approval process, but in general, Moldovian authorities tend to be very professional and supportive in solving such problems. However, the speed of patient recruitment in our IPR-EE clinical site in Moldova compensates for any time delay in the approval process.
Q. What are your future plans for IPR-EE ?
A. We have built up two highly motivated and well trained teams in both clinical sites to conduct Phase I and Phase IIa clinical studies in Ukraine and Moldova and we have established good relationships with the authorities in these countries. We would like to build on these strengths by partnering with pharma and biotech companies worldwide who wish to conduct clinical studies in healthy volunteers and special populations for good quality clinical studies and speedy patient recruitment. We will also look to expand our Phase IIb and Phase III clinical studies not only in Ukraine and Moldova but also other parts of Eastern Europe.
DR KARL ECKL , DR FRANZ JANIK, and DR NAHUM TSVITBAUM
Dr Karl Eckl is Executive and Medical Director of Innophar (IPR-EE). Trained as biophysicist and physician, he has more than 20 years experience in clinical research (email eckl@ipr-ee.com).
Dr Franz Janik is Executive Director and Director Business Development at IPR-EE. Trained as biologist and pharmacologist he has gained experience in pharmaceutical medicine and clinical research since 1987 email janik@ipr-ee.com).
Dr Nahum Tsvitbaum is the Deputy Executive and Medical Director of the IPR-EE clinical sites. He is an experienced anaesthetist and a clinical pharmacologist who held leading positions in major hospitals in Chernivtsi, Ukraine for more than 20 years.
