Clinical Trials in CEE: Harnessing the Potential

September 1, 2004

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-09-01-2004,

The EU Clinical Trials Directive may raise particular concerns for those considering running studies in CEE.

Clinical trialists, in their quest to find suitable patients for recruitment into studies in a timely fashion, have been recruiting investigators in Central and Eastern Europe (CEE) for over 10 years.1 In spite of many success stories, companies remain cautious about placing trials in these countries due to some other disappointments.2

Illustration: Paul Belci

Why consider CEE? As with other emerging clinical trial regions, the availability of patients meeting study selection criteria is the primary driver for considering CEE sites, often because the total number of patients and/or the speed of recruitment is insufficient elsewhere. Having made the decision that CEE should be considered, the final decision to invest in and then recruit CEE sites is often more complex. Secondary issues such as perceived regulatory difficulties, uncertainties of import rules, language, etc., can lead project teams to ask if the effort of working in CEE is still worth it. If the patients are available and add value to the study, the answer should still be "yes." But it can too easily become a "no" due to an ignorance of how to overcome the logistical issues.

Table 1. Investigator agreements

In this article, we discuss some basic strategies for ensuring that the the primary reason for recruiting in CEE —potential of sites and patients—is not lost through a lack of understanding of how to successfully organize the logistics, even if these secondary issues seem daunting. The article focuses on the nonprotocol study issues, and compares and contrasts organizing CEE studies with Western European experiences. We discuss those study logistics where CEE requires particular attention, and, using a worked example, present a comparison of some of the costs of operating in Central and Eastern versus Western Europe.

A categorization of study issues

The primary focus of this paper is to discuss what we define as "nonprotocol issues" of organizing CEE studies. However, meeting "protocol issues" is still paramount. We therefore assume for the purposes of this article that:

  • The potential CEE investigators have the right patients, equipment, facilities, correct basic training (CV), etc., to conduct the trial in the indication

  • The study can be run in the CEE country. (That is, if the CEE territory requires any particular protocol-related procedures or design then these are met, or if the CEE territory excludes particular protocol or designs then these are not part of the protocol.)

The nonprotocol issues considered here we group under the following three headings:

  • Regulatory

  • Logistics

  • Cost

We recognize that the protocol and nonprotocol split presented above is somewhat artificial, and in practice the issues are not so well differentiated. The above categories are, however, of value in comparing CEE with Western Europe. In our experience, clinical project teams with predominately Western European or North American training have a natural focus on protocol issues in their site selection and study initiation work, since nonprotocol issues have been "covered." When starting to work in emerging clinical trials regions, such as CEE, the relative importance of nonprotocol to protocol issues may not be so well understood (i.e., nonprotocol issues are not "covered" by default). The rest of the article presents and reviews these differences in detail.

Figure 1. Extract from ICH GCP.

Regulatory factors

Clinical trial regulations.

As in every country, CEE territories have local regulations governing the running of clinical trials. The details of each regulation are available from the authorities, and they include both specific and general business requirements, and are generally well-defined.5 Unlike in Western Europe, the "case histories" and guidelines for working with these regulations are not so widely published, and continue to present challenges to submitting study proposals for approval.11 Two problems often arise here. First, the level of documented procedural detail may be minimal or uncertain. Additional, undocumented steps may be required in practice. Failure to recognize this can cause delay at best, or rejection at worst.

Table 2. Basic study assumptions

Second, as in most countries, relevant requirements for running a trial may not be presented solely in the clinical trial regulations. For example, a recent trial in Hungary used a psychotropic agent as a comparator; the import of this drug was subject to both clinical trials regulations and controlled substance regulations. A separate process was required to be initiated and completed in parallel with the clinical trial approvals process.

It is also important to recognize that many of the CEE countries are seeking entry to the EU, and have been and continue to actively review their clinical trials regulations to meet EU requirements and/or GCP.3,4 Thus, at any point in time, both the regulations in force and the working practices designed to comply with them may be in a state of flux. These points require that local, up-to-date knowledge is available to the study team. Brunier's paper11 presents an overview of the main similarities and differences in 1999, and is still helpful as a starting point for understanding the previous and current requirements.

Figure 2. Graphs of calendar time advantage. (A) Equivalent start times. (B) Equivalent times for initializing patient recruitment. (C) Equivalent end times.

EU Clinical Trials Directive. The EU Clinical Trials Directive may raise particular concerns for those considering running studies in CEE in the period immediately after its effective date. Questions may be raised in two forms:

  • Has the directive been implemented?

and (if yes)

  • Has the administrative infrastructure been put in place by the authority to support the directive?

The deadline for the implementation of the European Clinical Trials Directive 2001/20/EC was 1 May 2004. The directive has been implemented in the majority of new accession countries, and is planned or pending in the others.12

What are the consequences for sponsors? As with any EU directive, if a member state has not completed implementation into its national law by the effective date, it is a matter for the Commission. In the eventuality that a member state (in CEE or otherwise) has not implemented the provisions of this directive, a sponsor cannot follow them. Following the member state's existing clinical trials approval process, obtaining ethics committee approval in the customary fashion, while adhering to the principles of the directive and ICH GCP, should reduce subsequent issues. Early discussions with the appropriate regulatory authorities is encouraged to develop a common and accepted position.

Table 3. Key differences

Concerning the administrative framework required in order to support the directive, time will be the arbiter. However, with the comparatively small number of studies being run in these countries (compared to Germany, say), and the stated desire on the part of some authorities to attract more research, it is hoped that the requirements will not prove too onerous.

For both of these issues, a more pertinent question for the sponsor is whether to take a more conservative approach towards new accession countries, compared to existing member states. In other words, if a major clinical trials country and a CEE country has either not implemented the directive, or is known not to have the administrative infrastructure in place, will the sponsor company consider them equitably?

GCP experience. GCP experience in CEE is often of concern to study teams. Increasingly, CEE investigators are obtaining GCP experience, but study teams still find themselves faced with excellent sites (from the patient perspective), and excellent physicians (including opinion leaders) without GCP experience. Is this a problem? First, are GCP experienced investigators a necessity? No, they are not. Investigators must be trained in GCP principles (and then follow them), but experience per se is not a requirement (see Figure 1), and should not, in our opinion, be a reason for excluding CEE from studies.

Table 4. Keeping all items constant, but reducing MV frequency in CEE

In practice, the issue of GCP can be addressed through including a mix of naive and experienced investigators in the study, with experienced investigators taking on a mentoring role, in combination with increased monitoring support. The alternative is to permanently exclude otherwise excellent investigators from studies (potentially for other pharma sponsors to utilize to their advantage). CEE investigators are highly committed and relatively small levels of investment can pay large dividends.2

Other regulations. The laws of CEE countries must be observed. Key legal issues relating to running a study in CEE are those involving the investigator contract and the type and methods of payment. These are summarized in the checklist (see Table 1) and are generally relevant throughout CEE. In practice, the details of what is or is not acceptable will be governed by a combination of local country general law, local GCP regulations, and investigator and/or institution rules and preferences.

The consequence of meeting CEE laws may be contracts and practices that are unfamiliar. For example, contract wording may end up deviating significantly from standard corporate wording. This may take significant internal debate. Local advice, and an acceptance that this may take time to resolve, are advised.

Similarly, some investigation of the legal issues relating to the import of CTM and the retention of staff should be made. In almost all CEE territories, a local agent is required for drug importation. If staff are to be engaged directly in a CEE territory to work on the project, either as freelancers or as a full employees, then local regulations must be followed. As discussed above for investigators, it is in the areas of contracts and payments that careful attention to local law is required (see Table 1).

Regulations in summary. The drug and wider business laws of many CEE countries are changing and/or may be best implemented utilizing undocumented procedures or conventions. When considering CEE countries, advice should be sought from local experts, and, if significant time has lapsed since the feasibility evaluation, confirmed prior to initiating activities.

Logistical factors

Good communication is a key factor in the success of any clinical trial, and attention to communications, written, telephonic, and travel, are important to success when operating in CEE. The three key areas of travel, post, and telecoms are discussed below.

Travel. Getting patients and CRAs to the right place at the right time is key to a study. Travel arrangements in CEE countries can be interesting, and should be reviewed carefully before committing to a particular site.

Patient travel.Travel for patients varies considerably in CEE. Throughout the world, rural populations have greater travel requirements than city dwellers, and this is more so in CEE. It is therefore natural to focus on capital cities as the starting point for site and patient recruitment, with their high-density populations. Moscow and Warsaw enjoy the best infrastructure in the Russian Federation and Poland, respectively, and also have high populations (20 million and 5 million, respectively). In contrast, Budapest has a population of only 1.5 million (the population in all of Hungary is only 10 million).

Perhaps more important from the patient point of view is the practical organization of many of the CEE health care systems. In many countries (such as Russia and Bulgaria), primary and specialist care is organized around very large hospitals serving very large populations. Once diagnosed, patients are quickly referred to specialists for treatment, or, as in France, they can go directly to the specialist without a referral. The key point here is that study subjects in these countries expect to travel to large specialist centers for treatment. This is of considerable advantage for clinical trials.

CRA travel. CRAs undertaking their monitoring duties also benefit from these arrangements. Journeys are shorter, time on site more productive, and several sites are often within easy reach within a single day. The problem is often the number of study subjects to be reviewed.

When CEE sites are not located so conveniently, travel can become much more of an issue, and may result in long and tedious journeys. For example, in the Czech Republic and Slovakia it may be organizationally efficient (to meet language requirements, say) to monitor sites in Bratislava from Prague. But Bratislava is a full day's travel (if not more) from Prague when journey and work time are considered, yet only one hour from Vienna.

The key test we apply for reviewing the CEE travel issues is to consider the unscheduled visit, whether this arises from adverse events, technical support or administrative requests. By reviewing how a site can be serviced will reveal any problems with travel. If travel times show that, for example, sites cannot be visited in line with regulatory timeframes, then a re-evaluation is probably necessary.

The value of each CEE site to the study therefore needs to be considered carefully to ensure that any travel difficulties or increased travel costs are compensated for by the contribution of the site to the study, and plans are in place to respond to the requirements of unforeseen travel. We therefore conclude that locating sites in large population centers is the best strategy for patient travel, and if the local work is sufficient, basing a CRA within the city will offer significant advantages.

Mail and packages. Careful consideration must be given to confirming how mail, packages, and other deliveries or pickups will be made. While robust in general, the postal and delivery infrastructures may not perform to service standards common elsewhere. Courier services may not be able to guarantee delivery times, sometimes due to the courier's own organizational issues and sometimes to "paperwork," of which customs clearance is the most significant for clinical trials in CEE. Close local attention to this is essential, even if a Western courier's headquarters have given assurances of support and service levels. Familiarity with the specialist needs of clinical trials by CEE courier services is often not as well developed, and may be completely lacking.

Our key test is the expected response to unscheduled requirements for pickups or deliveries. If, for example, courier times are long or unreliable, and critical samples have to be transported under particular conditions back to a central lab, prior understanding of how this can be achieved is essential to success. Contingency planning will help here to both respond to these issues should they arise, and to offer study teams clear approaches to balancing scheduled with unscheduled work.

Telephones, fax, and electronic communication. While considerable progress has been made over the past 10 years to improve the communications infrastructure in all CEE territories, it is still the case that large variations in equipment and service levels occur. It is therefore essential to review the electronic communications requirements against the studies requirements, especially when Internet (TCP/IP)-based services are required.

The general telephone (voice) infrastructure does not usually present an issue. Where the telephone infrastructure has been upgraded, it is often as good or better than comparable Western systems. In private buildings (field CRA locations, private clinics) or in more remote locations, older systems may still be present and need to be accommodated (buildings where the exchange has been upgraded, say, but the distribution to individual locations has not). Situations such as this may cause problems if, for example, an IVRS randomization system is to be used. If the telephone system itself is satisfactory, facsimile transmission will usually be unproblematic. But if fax technologies are essential to the study, provision of dedicated additional lines may result in a bureaucratic exercise with telecom providers.

Services for mobile phones are generally well supported in the capitals and large population centers throughout CEE. It should not be expected that mobile phone services will be available in rural or even some urban areas. Mobile phone services such as laptop connectivity should be checked if essential for supporting monitoring visits, as the service levels provided can be mixed, and may not be usable in some areas.

TCP/IP (Internet)-based services (email, Web browsing, etc.) using direct connections are widely available across CEE, and as discussed for telephones above, often now are based on the best available technologies. The types of coverage can vary widely, however, and if the reliance required is high (for EDC tools, for example) checks on speed, stability and configurations are essential prerequisites to initiating and training sites in the study specific tools. Capabilities can vary widely, even within limited geographical areas; there are examples of one district being served by broadband while its neighbor is not.

IT support. Of equal, if not greater, importance is access to technical service support. This should be checked carefully. In our experience, the best support in CEE is provided through local companies. The advantage that local knowledge brings must, however, be carefully weighed against the problems that can arise if attention to system requirements and regulations (e.g., maintenance computer systems validation status) are not met. This is not a major problem, but should be factored in when selecting support providers. Closely associated are the methods to be used to report, escalate, and resolve issues. Reporting problems to the CRA may be easy from a language and contact point of view, but if inadequate technical experience or delays in escalating to the technical groups occurs, sites can quickly become frustrated. Conversely, leaving sites to manage their own support services could lead to difficulties, especially as the level of technical competency can be very high in some of these countries: local technical solutions may unknowingly compromise regulatory (e.g., CSV) requirements. Although these issues are not related solely to CEE, if issues occur they can easily become more significant due to language and technical communications difficulties between sponsor, local study support, and local technical support teams.

Logistics in summary. Working in large population centers will optimize logistical considerations in relation to travel (both subject and sponsor), communications (postage and telecoms), and any requirements for more advanced IT services. Locally based support both for monitoring and other issues, preferably within the population center, will further expedite the processes.

Cost factors

Once a decision has been made on therapeutic, subject recruitment or regulatory grounds to use CEE sites, the cost of the study often becomes a next critical factor. As with any study, it is difficult to offer specific cost information without considering the specific details of the study. However, under current circumstances, CEE costs will tend to be less for the equivalent service in Western Europe.5 In the next section, we will review and compare direct and indirect costs between Central & Eastern and Western Europe. Direct costs are defined here as those costs with an immediate associated cash value, while for the discussion of indirect costs we will review some time-related factors, which have clear cost implications.

Direct costs. The three key costs reviewed here are investigator fees, expenses, and monitoring expenses.

Generalizations concerning investigator fees in CEE can usually be challenged by numerous specific examples, but so far we have not seen fees in CEE higher than in the West, and have often seen them much lower. The amount you pay will depend on a number of factors, aside from particular local circumstances. The sponsor's local affiliate will, in general, tend to keep the price down. The sponsor or CRO head office's involvement will tend to raise the price (although they may not recognize it), either due to a lack of local knowledge in negotiating, or because of a perceived need to pay all investigators in a multicountry clinical trial the same (or similar within a tight range). Sponsors are often uncomfortable that an investigator in the United States may receive three times the pay per patient for the same work compared to those in some CEE countries. Lastly, one must consider the investigator's expectations based on previous experience with Western sponsors (which will again tend to inflate the price). As with so many issues, this is always best handled by local agents, who will be able to negotiate a fair, low (compared to Western investigators) but motivational price, without engendering any bad feeling.

Concerning expenses, most equipment costs (such as a laptop) will follow international prices, and not be cheaper locally. Monitoring expenses will be much lower for a local monitor, however a Western monitor traveling on a co-monitoring visit may well experience prices similar to what they are used to in the West, as they will tend to stay in international hotels at standard rates. As stated above, careful thought must be given when considering sites away from capital or principal cities. The monitoring travel time can be considerable, as even local monitors can be reluctant to fly on some local airlines. Also, the time cost involved for a Western monitor on a co-monitoring visit or QA auditor must be considered.

Indirect costs. The most significant indirect costs associated with any clinical study are time related. Depending upon the details of how study resources are to be obtained, these costs may be visible (if using a CRO), or hidden (if using company representative office support that does not recharge costs).

One of the central factors in selecting CEE for a study is the rapid recruitment rates that can be achieved, with the goal of reducing development times. These goals, which are usually defined by the overall development plan, must be reflected in the timelines for each study. In the next section a typical sample study that might be undertaken in either CEE or Western Europe is compared and contrasted from a man-hours (cost) and calendar (elapsed) time perspective.

Cost in summary. To minimize costs, our advice is to do as much locally as possible, both the basic resourcing (e.g., CRAs) and the management (such as negotiation with investigators and local providers).

A worked study example

The study is to recruit 450 patients, and could be undertaken with equal clinical and research success in either CEE or Western Europe (see Table 2 for basic study parameters). The number of centers for each region is already decided: 30 study centers in Western Europe and 10 centers in CEE, this difference reflecting the greater number of patients that can be recruited in a single center in CEE (a factor of three in this example). The treatment period is four months (other values can of course be selected), resulting in a four-month period between the last patient recruited (LPI) to the last patient completed (LPO) in both regions. The recruitment rates (7.5 patents per center per month in CEE and 1.25 pts/ctr/mth Western Europe) chosen reflect our experience recruiting subjects for CNS studies. Others report similar relative differences in recruitment rates (~ x3 to x6), but associated with lower absolute rates (the study therapeutic area is not published).

6

Table 3 presents a comparison by region of a range of key time-based activities for this example study. First, it would be expected that the overall study start-up time in CEE countries would be extended, reflecting the (potentially) increased complexity of establishing the study's CEE regulatory requirements, study site contact, contract and other negotiations, and operational logistics. This extended timeframe for CEE sites may well be accompanied by a greater amount of site selection work, since CEE sites may not meet even basic requirements in areas such as telecom. In this example, the ratio of sites screened to sites initiated is 2.5 in CEE (i.e., 25 sites screened to eventually recruit 10) compared to 1.2 in Western Europe (36 sites screened to recruit 30). This is a lot of work, even if undertaken by telephone interview (however, often locally it is considered best done by visit). This has resulted in 14 site selection visits (SSV) to recruit 10 sites, in CEE in comparison with 33 SSVs to recruit 30 sites in Western Europe.

The number of site selection visits per site for CEE may well be increased to three, compared to the customary one. This is because of the increased training, the need to implement site support, and the need to negotiate a foreign contract, all of which take more time and are best done in person, rather than by telephone or letter.

Monitoring. Once the sites are initiated, the time required for subject recruitment is considerably less for CEE. In this example the recruitment time is half of that required for Western Europe (six months compared to 12 months), even though there are one-third the number of centers.

Due to the increased number of subjects per center and the increased center support required (in areas such as ongoing investigator training), the monitoring frequency may need to be as much as four times higher in CEE than the West. The example shows that 16 monitoring visits (MV) per site will be required by Western European sites, in contrast to 40 MVs per site in CEE. However, over the course of the whole study for all sites, this increased CEE rate, when combined with the reduced number of sites, results in a total of 480 MV to be undertaken in Western Europe, compared to 400 MV in CEE.

Finally, it is worth commenting that particular tasks for CEE sites do seem to require more hours to complete when compared to Western Europe. Three activities exhibiting these increases are shown in Table 3 that we have found by experience to need particular consideration. These are investigator grant negotiations, CEE directed project management tasks, and SAE management. These require, in our experience, approximately 2-2.5 more operational hours when CEE sites are involved than for Western sites.

Developing a budget. We can now use this sample study to evaluate the budgetary implications for the two regions. We use a simple model based on start-up time, site monitoring time, in-house monitoring time and project management. Leaving out other variables such as regulatory affairs, QA, and data management, we can then run the model for the two regions and observe the effect on the theoretical hours projection. The parameters and values presented in Table 2 and Table 3 are typical of the numbers used by CROs and clinical departments to calculate hours and monetary costs. Using a CRO style model incorporating each activity and the associated number of hours, an estimate of the overall hourly resource requirements has been made (Table 3, last line). This shows that the clinical operations hours estimates for Western Europe is 16,264 hours, and for CEE 11,968 hours, i.e., the CEE hours budget is 25% less.

Costing models of this type can be used to model "what-if" situations. All of the above changes have less cumulative effect on the budget than the single issue of increasing the number of monitoring visits. Table 4 shows the effect of keeping all items constant, but reducing the monitoring visit frequency back to Western levels. This has the result of decreasing the total hours required in CEE to less than half of the Western Europe.

However, a strategy of monitoring sites with Western Europe frequencies that have CEE patient recruitment rates is often a route cause of sponsor dissatisfaction with CEE sites. More patients per week at each site will take more time, and issues will accumulate more quickly. Longer visits at Western European frequency will not have the same efficiency as increased numbers of visits. Also, these investigators need more support. In fact, they welcome it. The consequence is that the number of visits may need to increase by more than the ratio of increase in the number of patients (as in our model). It may be that during the study a judgement can be made that this level of support can be reduced as confidence increases, however, the budget should not be predicated upon this.

Calendar time consequences. The potential time savings possible when using CEE sites can be exploited in various ways. These overall savings do not come through an equivalent reduction across all activities. As discussed above, study start-up and sites initiation activities tend to require more time (elapsed) and more resources, while recruitment periods tend to be shorter. Figure 6 presents the elapsed times for the sample study discussed above for both CEE and Western Europe (for the purpose of this article it is also assumed that the closure elapsed times are the same in the two regions).

Three "overlaps" of these timelines are shown. The combination of reduced overall operational hours plus shorter overall timelines in CEE territories gives the study project manager considerable scope in how to use CEE sites as part of a development program. For example, if a study or program demands Western Europe and CEE sites, then selection of a limited number of key Western sites, in combination with a majority of CEE sites, will both meet study regulatory requirements and optimize recruitment rates.

By adopting the timing strategy of Figure 2(a), the study will have the early experiences of Western European sites available to CEE before the main patient recruitment, while minimizing the number of sites to be closed to complete the whole study (since these will be a smaller number of Western European sites). For those not accustomed to working with CEE countries, it often causes concern when the CEE centers are seen to be initiating late.

Figure 2(b) shows a greatly improved completion date when it is possible to give local staff advanced warning of their probable participation in a trial. Many of the contractual, communications, and logistics issues can be discussed and resolved in advance of a finalized protocol, thus eliminating that initiation lag experienced in Figure 2(a). If employing this strategy, the ground rules for competitive patient recruitment CEE versus West must be clearly set, in order to avoid having some very dissatisfied Western investigators.

Another typical scenario where CEE sites can offer considerable advantage is to increase recruitment if expected rates fail elsewhere. Even with possibly extended start-up times, the reduced recruitment periods in CEE can recover a study timeline, where potentially the overall times if this approach is not adopted may now be twice the original estimates. Often a company's first introduction to CEE has been to rescue an ailing trial, and this graph will be more familiar [Figure 2(c)].

Price. The final price of a study undertaken in CEE will depend upon the hourly charge-out rates departments or service providers offer. In general, final prices should be lower and, if the charge-out rates are in line with national CEE salaries and costs, the combination of decreased total hours and reduced rates will offer significant advantages. If, however, the provider (CRO or pharma departments) uses a harmonized pricing policy across Europe, then savings through working in CEE can only be gained from a reduced number of hours required.

Salaries and other costs associated with establishment of an in-country entity (such as office rent) are generally lower in CEE than Western Europe. Prices vary greatly across the region, but even in the more expensive cities, such as Moscow, costs are lower. A detailed survey of costs across the region is beyond the scope of this article. As discussed above, the largest cost advantage can clearly be gained by placing the whole study in the hands of local staff, remunerated and charged at local rates. If projects including CEE countries are part of wider international programs and appoint Western Europe-based project managers, then the final CEE price may be inflated due to the allocation of Western Europe costs to CEE sites.

Worked example in summary. Our example has demonstrated that reducing the number of sites, but giving a greatly increased level of monitoring support per site, will result in a modest saving in the man-hours budget. However, the calendar time savings are impressive, and the budgetary savings can be translated into further monetary savings if the project is resourced locally. Our reasons for advocating this approach are that it represents the safest way of ensuring the overall objective is achieved: higher quality patient data more quickly.

Discussion and conclusions

Undertaking clinical trials in CEE can provide considerable advantages to project teams. The high numbers of quickly available, easily accessible patients provides the primary driver for considering this region.1,7,8 Because its geography and culture is similar to that found in Western Europe, combined with its investigator willingness and enthusiasm to contribute to drug development, working in CEE is less challenging than in more geographically distant emerging clinical trials areas. Finally, as discussed in this article, the organizational effort required for studies, and the regulatory framework, while different from that in Western Europe, should not present insurmountable challenges to the project team, and should not be the reason for rejecting CEE involvement in studies.

Three critical, nonprotocol, organizational issues relevant to operating in CEE have been presented and discussed here. From these, four general points for working with CEE sites emerge. These are 1) that local expertise is required to manage and support the key processes, and especially the regulatory requirements; 2) that a greater time investment in CEE sites will be required both before and during the study, 3) that attention to establishing the communications infrastructure is critical, and 4) that increased CEE resource requirements per site do not immediately equate to higher costs.

The benefits of using CEE sites then emerge in the form of rapid recruitment rates, high quality CRFs, and reduced costs, with minimal subsequent regulatory or clarification issues.6 However, these benefits do not emerge without careful attention to the process, procedures, and methods to be used. This is also the experience of others.9

For example, CEE sites and investigators may not be well acquainted with GCP. This means project teams need to invest more in start-up tasks such as training, which tends to extend the time to FPI. This extra time investment is rewarded subsequently by the numbers of patients then enrolled. Similarly, monitoring frequencies for CEE sites may need to be higher than for Western sites, but again, the extra investment in CRA time is rewarded by patient recruitment rates and the quality of the data.10 Appropriate choice of productivity-based project metrics will show this to be the case (e.g., queries/patient/site).6

The monetary costs of running a study in CEE can be very variable, and as elsewhere, will depend upon a wide range of cost variables that are highly study- or sponsor-specific. This makes it difficult to extract and present more helpful trends and points. However, the time (resource) requirements can be used to illustrate CEE trends. Using a sample study, we have illustrated the key resource issues of time and cost. Thus, increased setup times and monitoring frequencies are features of CEE studies when compared to similar Western European practice. This potentially negative feature is balanced by the subsequent increased rate of patient recruitment. These features enable CEE sites to support projects in a number of different ways. Studies recruiting slowly elsewhere may be able to regain time through the use of CEE sites. Additional studies, perhaps required due to findings or opportunities discovered after the original programs were developed, can be undertaken without compromising the final submission timelines. Optimized training programs can be developed based on early Western Europe experiences that are then transferred to the CEE sites that will recruit the majority of patients. These features of working with CEE investigators powerfully extend the range of options available to project teams charged with delivering to deadlines.

We feel that the use of local expertise is essential to successful delivery in CEE. Whether this is obtained directly by employing someone or through consultancy or CRO contracts, the currently changing regulatory and procedural environment is in a state of too much flux to enable sponsors outside the region to gain the required knowledge quickly enough. Since the issues arising here are so central to successful project delivery (and/or the issues presenting are too complex), failure to employ this strategy is often the basis for rejecting CEE involvement in a program. We feel this a poor reason to reject CEE involvement, given that all experience with this region shows that the primary rationale to be there can and will be met, and often exceeded.

In conclusion, CEE’s large pool of potential study subjects, able to deliver high-quality clinical research data, offers considerable advantages to drug development teams willing to work in the region. The numbers of studies now completed in this region with outcomes no worse than Western Europe, and some better than it, demonstrates that this is the case.5,6,10 However, the practical issues of placing and managing studies here still challenge many project teams. This does not have to be the case, since, as presented here, the issues are understood and only require appropriate planning. Failure to involve CEE sites in studies based on costs or logistics issues is, in our opinion, no longer a sufficient reason to reject working in this region. The proven advantages of access to such good patient populations will offset any difficulties that may occur along the way.

References

1. B.N. Natorff, “Clinical trials in Central/Eastern Europe: Industry viewpoint,”

Drug Information Journal

, 32, 129–133 (1998).

2. H. Neal, “The contract research organization perspective: Audits in Central and Eastern Europe European countries,” Drug Information Journal, 35, 475–480 (2001).

3. T.L. Paal, “Recent changes in clinical trial authorization in Eastern Europe,” Drug Information Journal, 31, 151–155 (1997).

4. N.B. Borissov et al., “Transition challenges for collaboration agreement of drug regulatory authorities in European Union associated countries: Focus on Bulgaria,” Drug Information Journal, 35, 935–939 (2001).

5. D. Babic and I. Kucerova, “Benchmarking Clinical Trials Practices in Central and Eastern Europe,” Applied Clinical Trials, 12 (5) 56–58 (2003).

6. P.G. Platonov et al., “Recruitment Rates and Data Quality-Are They Linked?” Applied Clinical Trials, 12 (11) 32–34 (2003).

7. N. Sinackevich and J.S. Tassignon, “Speeding the Critical Path,” Applied Clinical Trials, 13 (1) 42–48 (2004).

8. M.A. Gebska and J.R. Hargreaves, “Conducting Clinical Trials in Poland,” Applied Clinical Trials, 9 (4) 52–59 (2000).

9. J. Demeter, “Selecting Sites and Investigators: An Approach for Central and Eastern Europe,” Applied Clinical Trials, 11 (3) 56–66 (2002).

10. P. Platonov, “Clinical trials in Russia and Eastern Europe: Recruitment & quality,” International Journal of Clinical Pharmacology & Therapeutics, 41 (7) 277–280 (2003).

11. D.P. Brunier and G.R. Nahler, “Submission of Clinical Projects to European Ethics Committees,” Applied Clinical Trials, 8 (4) 49–57 (1999).

12. B. Goldberg, “EU GCP Directive 2001/20/EC and the New EU Member States,” DIA Forum, 40 (3) 6–7 (2004).