Two decades on since clinical trial services started to expand in Central and Eastern-European (CEE) countries, the region is still in a position to offer unique characteristics and well recognized features that maintain the location as a focus for innovative drug research trials.
Patient access and healthcare characteristics are two of these major aspects, but also stabilized start-up rules and regulations, make the CEE region attractive. Oncology research is one area that can be supported by, and benefit greatly from, these positive clinical trial criteria.
Within the past decade, specific efforts have been made to expand the list of countries where clinical trials can be conducted, taking into account two major features: firstly, the prompt availability of mainly treatment-naïve patients willing to participate in clinical trials; and secondly, the relevant disease profile for targeted therapeutic areas. This expansion has resulted in a shift away from the traditional clinical trials markets of North America and Western Europe, where thirty years ago, the vast majority of trials were conducted, compared to less than two-thirds as of today (Glickman 2007; Novak 2014).
It was anticipated that the BRIC countries (Brazil, Russia, India and China) would grow rapidly and become responsible for the majority of trial conduct, but the actual growth rate was much lower. Recent data, based on the number of clinical sites set up within countries, has shown significant attention being paid to the CEE region, with a reported growth rate in the region of over 12% in 5 years (Misik 2014).
The CEE region represents a population of approximately 340 million inhabitants across 20 countries, each with differences within population and clinical trial heritage. With these resources it was inevitable that a number of CEE countries have established themselves within the top 10-15 countries on the global list. However, this growth is not based not solely on the hard parameters, such as geography, population size or costs; but also on a number of other “soft” factors, such as the supportive environments, access to qualified local staff, and recognized motivational factors of all stakeholders.
Country Selection For Patient Access
Centralized healthcare and national health insurance systems are common throughout Eastern Europe and so patients tend to be funneled into specialized medical centers in each country. These hospitals treat a large number of patients at one site, with a wide ranging medical team and multiple diagnostic opportunities. The population and the treatment regimes in Eastern European countries remain more homogeneous than those in North America and Western Europe, making it easier for a study team conducting a trial to identify patients who meet protocol in/ex criteria.
One of the most recognized potential benefits for the patients who participate in clinical trials is the access to cutting-edge medications. Because of the centralized healthcare and a shortage of funds within the national health insurance system, there is ever-growing competition between patients to gain access to advanced therapies supported by the reimbursement system. Since the most recent and most advanced modern therapies are not covered by national reimbursed programs, the willingness of patient participation is increased. This level of eagerness affords many treatment-naïve patients to be available for clinical trials from the population. This is advantageous, especially within many of the newest oncology trials, where the designs focus on selecting specific candidates from within the patient pools. The oncology care coverage network in each country is based on National Oncology Centers and University Hospitals, plus several regional hospitals with oncology departments across the country. The number of potential clinical sites varies according to the size of each country, but it is the range of 12-15 sites for mid-sized CEE countries such as the Czech Republic, Hungary, Romania, and 15-25 for Poland. Most of them take part in those 80-120 ongoing clinical trials as this number is based on the average number of interventional trials listed in EU Clinical Trial register within the therapeutic indication “oncology”. Within this national oncology therapeutic network the coverage of almost 100% of the patients are seen in real clinical practice.
Industry statistics released within the last decade suggested that approximately 40-50% of sites fail to meet enrolment targets within the western clinical trials environment for phase II and phase III trials, and more alarmingly, 11% of sites fail to enroll a single patient in a clinical trial (Li 2008; Tuft Impact 2013). This obviously results in a significant waste of human and financial resources, and also causes huge disruption to developmental timelines. Within the CEE, and specifically in Eastern European countries, the greater potential patient participation in clinical trials increases the number of treatment options, and consequently reduces the costs to the national healthcare system. Therefore, not only are the patients motivated to participate in trials, but also the investigators and hospitals, as each stands to benefit. The choice of countries in which to conduct trials is a potentially costly decision, as evidenced by recent research indicators: delay in site activation may account for up-to two-thirds of valuable enrolment time (Dutton 2015).
Regulatory Aspects – Growing EMA Compliance
The implications of the implementation of European Medicines Agency (EMA) regulations are complex and wide reaching, but it is recognized by historical data that clinical research is strongly supported by regulatory environments that include a transparent regulatory process and predictable start-up timelines. Eastern Europe includes nations that are within the European Union (EU) and adhere to EMA guidelines, and those which have their own internal standards, such as Russia, Ukraine, Serbia and Turkey. The EU-member states which are also placed within the most popular countries active in clinical trials, such as the Czech Republic, Hungary, Poland and Romania, are fully compliant with the EU directives and they are ready to implement the new Regulation No. 536/2014. In some aspects, such as the combined Regulatory and Ethical (“single-route”) submission – which has already been implemented in Hungary – the result is a much more predictable 55-60 day timeline and simplified approval procedures.
Study Start-Up (SSU) is very complex, and is recognized as a bottleneck where functions are performed by multiple people, in multiple locations and also at the site levels. Delays in clinical trial timelines were often considered an embedded risk especially when outside of US or the Western-EU countries. One of the well-recognized risks of SSU is the lack of local, trained staff with the knowledge of procedures involved in the process. As it is today, study sites within hospitals or academic institutions are managing the procedural parts through their clinical coordination offices, which can provide details of requested and optional elements to the Sponsor.
Within the CRO environment, when a defined local start-up team is able to manage all the country and site specific aspects, it is possible to “jump-start” trials at the site level and work in a very targeted manner to accelerate enrolment, and ultimately, patients can begin trials more quickly.
Higher Stakeholder Adherence For Better Clinical Data Quality
Since the environment within CEE countries increases both the patients’ and investigators’ motivation to participate in clinical trials, adherence to treatments and protocols are well accepted. As a direct consequence of clinical trial conduct, higher compliance and lower drop-out rates are expected in most of the CEE countries compared to Western countries. Clinical trials are also considered as highly innovative research activity, which contribute to the advanced, new modern therapies in medicine. Investigators and researchers who are involved in clinical trials also gain an opportunity to gather unique knowledge and achieve international experience in particular areas of medical science through having access to new treatments.
Based on the FDA’s publicly accessible Clinical Investigator Inspection List, the analysis of findings and outcome classifications from FDA inspections during Investigational New Drug (IND) studies was published, and showed better overall figures for the CEE region to those from Western European countries and the USA. Over 230 FDA inspections were conducted within the CEE countries, and the results indicated that the number of studies where “no deficiencies” were noted was double the number compared to Western Europe and the USA, and moreover, there were 15-26% less Voluntary Action Indications compared to results in developed countries. In Hungary, within the examined period (1994-2010), there were no official actions indicated. The average numbers of deficiencies per inspection were 1.99, 0.99, 1.59, and 1.49 for Western Europe, CEE, the USA, and for the rest of the world respectively. In short, the FDA’s site inspections reported fewer findings concerning protocol compliance and record keeping, and also reported fewer issues with informed consent documents and procedures. Checking the drug accountability and reporting adverse events resulted in better procedural compliance than inspections performed in Western Europe, the USA or other parts of the world. These data suggest that the high productivity of CEE sites is accompanied by regulatory compliance and clinical data quality that overall “is not inferior to those in Western countries” (Caldron 2012; Karlberg JPE 2009).
This regulatory acceptance and validation demonstrates that utilizing properly selected and trained clinical sites in Central and Eastern Europe can deliver high-quality data in a timely manner, and the additional costs of study-specific training and the translation of trial protocols and other materials into local languages are outweighed by the benefits in adherence.
One of the greatest challenges in clinical trial execution is the site (and country) selection process, and identifying a sufficient number of good quality sites and investigators to conduct the trial. To meet the expectations of the trial, the principal investigator (PI) should have a number of essential characteristics, including excellent medical skills in the therapeutic area of concern, an obvious commitment to research, access to acceptable facilities and time and willingness to continuously contribute during the study period. This will also include aspects around the administration and, participating on web conferences, study specific trainings, etc. Above all however, the PI must have access to patients who fit the in/ex criteria - based on selection standards - and will agree to participate in all required visits and tests.
From the CRO perspective, there is a prediction on clinical quality indicators when assessing potential sites/partners to perform the study. These include:
- Experience of the staff, PI, study team, etc. at the facility
- A proven track record in a therapeutic field in a specific country
- Identifying people that have already undertaken trials in that country with a proven track record in start-up and a demonstration of previous metrics such as time to site activation for previously completed trials
- Statistics on patients enrolled in trials/completed enrolment/ duration of patient enrolment
- Assessment of the risk of “over-promising” and “under- delivering” in real timelines
Features of resolution are often used in the tracking of investigators and the investigator site’s potential through performance indicators within an integrated clinical trials management system. There are known parameters that drive an investigator site’s potential performance, but in reality, it is complicated by the means of access to real enrolment data of clinical trials by other sponsors. Many people have tried to utilize these parameters to help them to choose sites with better potential to deliver more patients. Their success has been limited because of insufficient data to support any one of these parameters, and more importantly, because of the lack of structures and/or models to organically coordinate and integrate them.
It is important in the CEE to build up and manage the aspects of relationship not only between PI and Sponsor, but also between the site and the CRO. These are top priorities in the process of building trust and mutual recognition. The working relationship and the knowledge are the key aspects; this is dedicated work and still needs personal contact through dedicated local experts. Relationships cannot be built efficiently through an investigators portal alone, and that personal element is more evident within the CEE investigators, compared to US sites.
Examples of how partnerships work well include the Medical Center HDF in Budapest, Hungary, which is a regionally centralized hospital with 1,800 beds including an SGS-dedicated Phase I trial unit and has access to 2 million residents. The oncology department, which has 84 beds, is led by Professor Zsuzsanna Papai and has conducted over 360 clinical trials since 2011. SGS has set up a successful partnership with the HDF hospital which ensures a fast study start, a high quality of clinical trial data collection with a reliable and quick patient enrolment time. SGS experience extends to over 150 oncology drug development projects covering a broad range of cancer tumor types. Combined with an extensive site network SGS can address the specific needs and complexities of oncology clinical trial programs.
Additionally, the “Maria Skłodowska Curie Memorial Cancer Centre and Institute of Oncology” (MCMCC) is based in Warsaw, Poland, and is one of the leading regional comprehensive cancer centers. The Institute is dedicated to oncology research and has a 656 bed capacity, with 28 specialized clinical departments responsible for the diagnosis and therapy of various solid tumors types and provides diagnostic features. MCMCC has participated in numerous clinical trials (phase II and III) and translational research in close cooperation with international research groups (e.g. the European Organization for Research and Treatment of Cancer (EORTC) and pharmaceutical-company sponsored trials.
Operational Challenges In Oncology Trials
Operational challenges are even more critical to manage in oncology trials, since the patient costs are much higher compared to other Investigational Medicinal Products (IMPs). On the other hand, due to the nature of the medical conditions in these trials, it is necessary to investigate the best available options to manage the patient, maintaining their quality of life and minimizing the trial-related disruptions. In this respect, in order to be able to benefit from what is still a “naïve” place for oncology trials, an efficient partnership between the site, the sponsor and the CRO must be in place.
Based on these facts, and implementing late phase trials, but also developing local facilities for phase I and II/a trials, and consequently involving, training and encouraging young oncologists, will serve to further develop cancer research in CEE countries.
The Impact For Oncology Trials
In this region, multidisciplinary cancer care has a long-standing tradition, with the research groups in the CEE tending to work collaboratively with other research groups, including the EORTC. Researchers from CEE and institutional research centers improve collaboration with the rest of Europe. It is also important to mention that cancer research in CEE countries receives significantly less funding compared to high-income European countries. The shortage of funds comes from a lack of charitable organizations dedicated to cancer research, plus the relatively limited national research grants. This has resulted in the decline of academic-, investigator- and/or collaborative-group–driven clinical research.
Most of these CEE countries have nationwide cancer registries and regional cancer centers with multidisciplinary facilities and well-trained staff. According to statistics, non-communicable diseases, represented mainly by cancer and heart conditions, are becoming more and more significant healthcare issues in multiple CEE countries: most of the CEE countries are below the EU average: with Hungary and Croatia leading these negative statistics in all cancer mortality cases (Eurostat Data: age-standardized figures). Significant differences in incidence and mortality have been observed between European countries and the incidence of certain cancer types is higher in Western European countries, however, the mortality rate is generally higher in Central and Eastern Europe (Vrdoljak 2016). Within the therapeutic areas of all trials, oncology indications are dominating in Hungary and Poland (25-27%), but even presented a significant share (in average 22.2%) of all trials ongoing within CEE countries (data compiled from EU Clinical Trials Register 2016).
The most recent number of ongoing oncology trials implemented to CEE region is shown in Table 1, using data obtained from the EU Clinical Trial Register. The number of clinical trials with the indication field “oncology” is shown alongside the relative share within Europe (%) for the country.
Table 1. Oncology Clinical Studies in Europe (Ongoing) 2014-2016. (EU Clinical Trials Register)
*Data only for the period of Jan-Nov period included.
The data shows Hungary and Poland are the leading countries from the CEE countries, followed by the Czech Republic. These three countries contribute a significant 13.4-14.0% of European oncology trials, whereas the full CEE region represents between one quarter and one fifth of all European oncology trials. However, not only is the number of ongoing trials indicative, but rather the number of enrolled patients is considered as another key element of country selection. That ratio varies between 1.5x to 12x in most of oncology indications, but consistently higher compared to Western European sites. This data highlights the importance of the contributions these three CEE countries, and demonstrates the capacity and capabilities to conduct international multicentre oncology clinical trials in various indications.
Figure 1 indicates the number of ongoing oncology trials in 2016 within Europe, and shows Hungary has a comparable share of oncology trials to Austria, Denmark and Belgium, demonstrating the similar capacity and contributions in this field. The other leading CEE countries such as Poland and Czech Republic are also placed within the first 10 positions.
Fig 1: Ranking in Oncology Clinical Studies (trials ongoing in EU Clinical Trials Register, 2016)
Clinical research in the CEE countries has a long-standing tradition and well-recognized study experience in certain countries, such as the Czech Republic, Hungary and Poland. These countries have proven clinical research quality and patient recruitment potential within the emerging regions, and with the expansion to other CEE and EE countries, that would provide an access of population approximately 340 million for clinical development programs.
The availability of patients in these countries with certain medical conditions which meet study selection criteria, and their willingness to participate are the primary drivers behind considering CEE sites. Investigators and study teams within the region are motivated to partake in trials, for not only the medicinal benefits, but also the scientific opportunities trials bring in creating links with the wider international medical community. As a result, inclusion of the CEE region into a trial design provides a wider population pool to achieve the desired number of participants, and can help to speed up the recruitment which may otherwise be insufficient if restricted to just the USA and Western European sites. Eastern Europe is considered a “new bright spot” for oncology clinical trials by offering significant opportunities and the fewest challenges of any of the emerging regions, according to a recent survey of pharmaceutical executives cited by G. Dutton (2015).
Additionally, the growth of trial opportunities is also supported by the region’s national opinion leaders in medical fields, since participation promotes knowledge exchange and the continuous improvement of healthcare standards in Eastern Europe. With all the advantages the region has in terms of hospital infrastructure, stakeholder commitment and the somewhat lower costs, Central and Eastern Europe remains an attractive solution to conduct clinical trials. Where there are challenges, management of these with expert and local knowledge, alongside proper planning can mitigate the risks, but ensures the overriding advantages can be maximized.
For more information about SGS oncology services.
Dr. Istvan Udvaros, SGS Clinical Research Medical Director
Dr. Bela E Toth, SGS Consultant
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