The first U.S. investigational new drug (IND) clinical trials outside of the United States were conducted in Europe in the late 1970s. In the early 1990s, Central and Eastern Europe (CEE), Latin America, Asia, and selected countries on the African continent (mostly South Africa) became involved in clinical trials. 

The large pharmaceutical companies have actively recruited in regions outside the United States for their multinational trials.

  However, it appears that the smaller American biotech companies have been more cautious. New classes of drugs

  have appeared that include the participation of investigators from CEE, Latin America, and Asia. 

This makes it even more important to have a reliable, open information source that can offer an unbiased assessment of investigator performance worldwide. The U.S. Food and Drug Administration (FDA) is the only regulatory authority which maintains an open register of all inspections, i.e., inspections performed as a part of the Bioresearch Monitoring Program

  in other countries where U.S. IND trials are conducted. The Clinical Investigator Inspection List maintained by the Center for Drug Evaluation and Research covers inspections performed in 56 countries since 1977. As of 2004, the latest inspections have taken place in the Baltic countries Estonia, Latvia, and Lithuania, recent entries into the European Union. 

Last year, we published a review of available information on the quality of data coming from CEE and compared it with other regions.

  We have expanded the scope of this paper to include the nature of deficiencies reported from different regions. This analysis may help to identify the regions of concern for pharmaceutical companies and contract research organizations (CROs) responsible for the management of clinical trials. 

FDA inspections in Eastern Europe began in 1994. We selected this 10-year period as a logical place to begin our analysis of good clinical practice (GCP) compliance. Inspections dated from January 1, 1994 onward were selected for analysis. We believed it was especially important to select the same time window for analysis of inspection outcomes in different regions because of the ongoing development of ICH GCP guidelines. 

 Figure 1. Outcomes of inspections conducted outside of the United States since January 1, 1994 in the four largest regions. Data from the United States for the same period are given for comparison (left). The Asia region is not included in the diagram due to the low number of inspections performed during this period (8). Numbers in the centers of the pie diagrams indicate total number of inspections per region. 						

In total, data from 3178 inspections whose files have been closed with a final classification as of  4 May, 2004 were reviewed. Of all these, 2765 inspections were performed in the United States, and 413 in non-U.S. sites. 

We grouped countries into several regions based on the geographical principle and compared their performance with the corresponding data from the United States for the same period: 					

Asia: China, Hong Kong, Taiwan, Thailand, and the Philippines

Africa: Gabon, Kenya, Malawi, Nigeria, South Africa, and Zambia

Western Europe: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, the Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, and the United Kingdom

Eastern Europe: Czech Republic, Croatia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Russia, and Slovenia

Latin America: Argentina, Brazil, Chile, Costa Rica, Guatemala, Mexico, Peru, and Panama

West: Australia, Canada, and New Zealand.

We did not consider the Middle East as a representative region due to the low number of inspections (one in each country), and therefore we have not included it in further calculations. The data concerning the African region should also be interpreted with caution, since the vast majority of inspections (19 of 24) were performed in South Africa, which perhaps is not representative for the entire continent.  

Inspection outcomes were compared by three variables: classification codes, deficiency codes defined by FDA,

 and average number of deficiencies per inspection. 

 Figure 2. Nature of findings reported in the major non-U.S. regions compared with the USA data. Numbers in the centers of the pie diagrams indicate total number of findings per regions.						

I. Classification Code: Inspections of clinical investigators are classified to reflect the compliance status of the inspectee at the time of the inspection, and the classification describes the recommended actions that should be taken, either by the inspectee or by the FDA, as a result of the inspection. There are three basic classifications: 					

—No objectionable conditions or practices were found during the inspection.

—Objectionable conditions were found but the problems do not justify further regulatory action. Any corrective action is left to the investigator to take voluntarily.

—Objectionable conditions were found and regulatory and/or administrative sanctions by FDA are indicated.

II. Deficiency Code: the description of the inspection deficiency. 					

09: Unapproved use of drug before IND submission

10: Inappropriate delegation of authority

11: Inappropriate use/commercialization of IND

12: Failure to list additional investigators on 1572

13: Patients receiving simultaneous investigational drugs

14: Failure to obtain or document IRB approval if necessary

15: Failure to notify IRB of changes, failure to submit progress reports, etc.

III. The third variable used for comparison was the mean number of findings per inspections calculated as number of VAI and OAI deficiencies divided by total number of inspections. 

It is not often FDA inspectors return home without findings. The No Action Indicated (NAI) code is assigned to inspections that do not require any follow-up. This can be due to finding insignificant or no deficiencies upon inspection. 

Table 1. FDA inspection statistics for the major world regions 			

However, the Official Action Indicated (OAI) code is assigned to findings that were considered serious, significant, and that could jeopardize validity of study data. FDA data shows that the most common reasons for OAI codes during the defined period were failure to obtain patient informed consent or an inadequate consent form (16% of all OAI codes), inadequate drug accountability (12%), failure to adhere to protocol (20%), and inadequate and incorrect records (21%). 

In this analysis, we used the NAI and OAI inspections to assess site performance. We calculated the weight of NAI and OAI inspections among all inspections performed in a region. FDA findings are not a pure index of investigator performance, but rather a composite indicator of study management and QA/QC procedures implemented by pharmaceutical companies and CROs. 

Articles

Feature Article

The first U.S. investigational new drug (IND) clinical trials outside of the United States were conducted in Europe in the late 1970s. In the early 1990s, Central and Eastern Europe (CEE), Latin America, Asia, and selected countries on the African continent (mostly South Africa) became involved in clinical trials.

FDA inspections Outside the USA: An Eastern European Perspective

Paging your subject, paging your subject: here's a way to have everyone remember to be beeping compliant 

 (Madison, WI) turned to an existing technology to remind subjects to stay compliant with their medication. It used the pager, which originally was used because cell phones were too costly and bulky for carrying. 			

Trial subjects, Interspond believes, want to be compliant. They just forget: human subjects are human, after all. Remind then to swallow a pill and record any adverse events, and they'll be dependable. The 1.5-way pager is nothing more than a portable instant-messenger window, which Interspond "IMs" at each subject's specific compliance times. They respond by choosing "took it," "taking it," "will take soon" or "can't take it."  

The pager a subject is given at the trial site goes off twice, so subjects know what to expect. Once the subject is home, Interspond pages them whenever the study protocol demands it: time to take a pill, or conduct a reading, or begin a new diary. If subjects leave the beeper at home, the lack of response will be noted as noncompliance. Subjects who want to be compliant but can never remember have gentle nudges to help them along. 

The site receives weekly statistics of response rates, which can be matched up to compliance figures from diaries. 

Do your homework regarding your sites' technological capabilities before buying the EDC system 

 (Media, PA) knows that the compliance of subjects who take their doses on time is crucial for a study. An even more crucial type of compliance is the compliance of the individual sites for trial sites considering a switch to EDC. It takes hardware and software requirements for such compliance, though, not just positive attitudes and a willingness to learn.  			

With that in mind, it created VISTAâ¢, the Verifiable Investigative Site Technology Assessment. VISTA can determine the existing computer hardware and software at a site, by running an audit of each computer's features. It's simple enough for anyone to run in minutes, and it produces results quicker, cheaper, and often more accurately than a phone or paper-based assessment survey. Doing so will give trial site personnel an accurate view of what each site has and what it doesn't, helping determine how much an EDC switch would truly cost. 

A good EDC product will save money and time, and produce better results than paper. Making sure the implementation of the EDC system goes smoothly could be a more important decision than the choice of an EDC system itself.  

Scientific Software Tools, Inc., (601) 891-1640,

Check out a subject's history of adverse drug reaction, even for drugs that aren't on the market yet 

 (Kuopio, Finland) is not the first company to delve into pharmacogenetics, but it is one of the first to come up with a PG service for the clinical trial world. 					

DrugMEt is a microarray-based genetic test that searches eight different genes for drug metabolizing enzymes. If a subject has too many or too few of them present, they could be at a higher risk for an adverse event, end up being nonrespondent to the study drug.  

No two people will react to a chemical in the exact same way. By eliminating the extreme ends of the bell curve of efficacy, DrugMEt can help trial sites focus their energy on the majority of the patient population who can safely use the study drug, not the adverse event cases. 

Jurilab was able to develop this due to its extensive research into the East Finland Founder Population, a genetically homogeneous population.  

One day, tests such as Jurilab's will be as commonplace as a blood pressure reading or an alcohol swab. For the present, the brave volunteers of clinical trials get to have them first.  

News

Interspond’s RxPaging, Scientific Software Tools, Inc.’s VISTA, and Jurilab’s DrugMEt.

eShowcase

I've recently reviewed many articles on subject recruitment, retention, and attrition in clinical trials. I have found the same three basic research methods: surveys (by telephone and in person), interviews, and focus groups. The information gathered from the three methods include demographics, willingness to participate, problems experienced in clinical trials, motivations for volunteering, health behaviors, social support, benefit expectations, and understanding of the research project. But such strategies collect only the most superficial data, so we don't know nearly as much about the clinical trial experience as we need to know.  

, Harvard professor Gerald Zaltman explains why traditional market research methods such as surveys, interviews, and focus groups—the methods often used to study the clinical trial experience—are of limited effectiveness, and what market researchers should be doing instead. Table 1 summarizes Zaltman's market research myths and market research realities, which I've adapted to the clinical trial experience. 

One way to increase our understanding is to consider the recruitment and informed consent process as a marketing and sales presentation, in which prospective subjects offer their bodies and minds in exchange for an experimental drug or device. In this way, they can also be viewed as customers who have to make a buying decision. Do they "buy into" a clinical trial or not? From that perspective, emerging market research (realities) should replace traditional research strategies (myths) so that researchers can better understand the complexities of the clinical trial experience from a discipline that knows how to study customer behavior. 

 Table 1  Myths and realities in clinical trial research			

The 21st century demands that clinical trials be understood using 21st century market research methods. Clinical trials can't be done without subjects, and subjects won't be recruited or retained unless sponsors and researchers are willing to incorporate new research strategies to better understand the complex nature of the clinical trial experience. 

A Closing Thought

I've recently reviewed many articles on subject recruitment, retention, and attrition in clinical trials. I have found the same three basic research methods: surveys (by telephone and in person), interviews, and focus groups. The information gathered from the three methods include demographics, willingness to participate, problems experienced in clinical trials, motivations for volunteering, health behaviors, social support, benefit expectations, and understanding of the research project. But such strategies collect only the most superficial data, so we don't know nearly as much about the clinical trial experience as we need to know.

What Do We Know About Clinical Trials?

There are many publications concerning critical appraisal of medical literature in the current push for the practice of evidence-based medicine.

  These publications also address the issues of improving the reporting of clinical trial results

  and of improving statistical aspects of trial design.

  There is, however, little published on the importance of a thorough review of clinical trial protocols to identify potential problems prior to their initiation, or on the issues important for a clinical trial site and its investigators when assessing whether or not to participate in an industry-sponsored study. In this review, we discuss issues that we have identified when appraising a protocol and propose a template for appraisal of trial protocols from the perspective of a clinical study site. 

The design and performance of each experimental procedure in humans should be clearly formulated in an experimental protocol.

A trial sets out to answer one or more questions or objectives that are presented as hypotheses amenable to statistical evaluation. The protocol states the objectives of the trial, provides a rationale for answering the proposed question, and describes the procedures that will be used to answer the study question. It should be detailed enough to allow the trial to be conducted by any appropriately qualified investigators. The protocol will be subject to regulatory and ethical review and should conform to relevant local regulatory standards and other guidelines. The typical protocol contents are listed in Table 1. 

When reviewing a protocol, it is worth considering the questions in Table 2. The scientific questions in this list deal with the merit of the trial hypothesis. The fundamental question of randomized controlled trials is, "Does the new treatment differ from the old treatment and, if so, how and by how much?" While the relative importance of the trial question is generally obvious, the real potential of a new treatment is difficult to assess objectively. Promising preclinical and early clinical data can lead to unrealistic expectations for a new drug, particularly when preclinical models are not a true reflection of 

 biology. With accelerated drug development timelines, there is increased potential for indicators of drug failure being overlooked. Failure of the pivotal Phase III trials of gefitinib (AstraZeneca's Iressa) to demonstrate a benefit in the first-line treatment of nonsmall cell lung cancer is a classic example of a potential blockbuster failing to meet high expectations.

If trials aim to prove that a new treatment can improve on the existing standard of care, then a threshold for acceptance of the new treatment needs to be considered. This holds true for the increasingly common trials examining the equivalence of two treatments. Technically, statistical significance is important but for clinicians and patients, the magnitude of clinical benefit and the risk/benefit profile of the intervention are more important. A new cancer treatment that produces a statistically significant survival benefit of four weeks at the expense of excessive toxicity and impaired quality of life is not a major breakthrough. Investigators need to be clear in their own mind what constitutes a clinically important benefit and whether the proposed trial might be able to detect such a benefit. The difference between expected relative improvements and expected absolute improvements must be recalled. In a recent study of gabapentin for chronic headache, a 9.1% reduction of days with headache was reported.

  In practice this could translate to 1.5 days less each month; whether this is a clinically important and a cost-effective treatment is clearly debatable. 

 Table 1. Clinical Trial Protocol Contents, adapted from ICH Guideline for Good Clinical Practice7 			

Medical research involving humans must not only conform to generally accepted scientific principles but also be based on a thorough knowledge of the scientific literature or other relevant sources of information, and on adequate laboratory or animal experimentation.

The rationale for undertaking a study must be clearly described. A good background section should discuss the reasons for undertaking the trial, and the potential adverse consequences of participation based on the currently available data. If this is not included in the protocol, the Investigators Brochure usually provides a more comprehensive safety review. The investigator must remember that for new drugs the overall amount of information on efficacy and safety is small and potentially subject to the biases of small sample size. 

The control arm of a study should represent the medical standard of care and, therefore, the most ethically acceptable treatment. However, in some circumstances there may be no accepted standard of care due to a lack of prior evidence; variable patterns of care or differing opinions between institutions, countries, or individual practitioners; or the existence of apparently equivalent treatment options. While one could argue that the trial may establish the optimal treatment, if the standard comparator arm is unacceptable to the investigator it would be inappropriate for the investigator to undertake the trial. In the case of multidisciplinary interventions, all parties should agree that the trial treatments are acceptable, otherwise recruitment could be significantly compromised. Local practices may make adopting the protocol-defined standard of care impractical, particularly when the re-imbursement for the standard of care may vary substantially from country to country. This may result in study budgets being acceptable in one country but not another. 

Each stage of drug development raises different questions addressed by specific trial designs. Phase I trials assess safety and help determine treatment dose and schedule for subsequent studies, Phase II trials aim to assess efficacy in terms of response or a surrogate marker of response, and Phase III trials are usually comparative efficacy studies. Randomized Phase II trials are the most confusing. These studies usually serve one of two purposes; either determining likely efficacy compared to a comparator, or establishing the optimal dose or schedule for a new therapy. Information derived from Phase II studies is used to design subsequent Phase III trials. Phase IV trials also raise confusion: These trials may be observational studies or randomized trials and serve the purpose of expanding the information base related to a drug, whether from the perspective of efficacy, including new indications, or safety. Phase IV trials are often used as expanded access schemes for new medicines, and in our experience can cause problems related to ongoing drug supply at study termination and sometimes inadequate remuneration relative to workload. 

Table 2. Template for critical appraisal of clinical trial protocols from the perspective of a clinical study site						

The protocol should describe the randomization process and any processes to minimize systematic bias, as this can influence practical aspects of the study. The physical method of randomization needs to be clearly explained and reliable, especially when the randomization is centralized and accessed by computer or phone across multiple time zones. Blinding to the intervention received is an important method for minimizing bias. However, this may not always be appropriate or achievable, especially in the case of some intravenous therapies, where for safety and logistical reasons absolute blinding is sometimes impossible. Recently, our site declined participation in a trial as the investigators felt that the safety concerns related to blinding of a potentially toxic intravenous agent outweighed the importance of the study question. 

The method of administration of treatment is generally well described, but often the guidelines for treatment modification are insufficiently detailed and can lead to unexpected protocol violations. The best way to determine the usability of the treatment instructions, and the protocol in general, is to consult the users, such as trial coordinators, nursing staff, and pharmacists. Clarifying these concerns with the sponsor prior to study initiation will often resolve the issue, sometimes through protocol amendment. 

Study population and eligibility criteria

Eligibility criteria serve to identify the target population and exclude patients that potentially could be harmed by the treatments or confound the results of the study. Investigators should carefully consider the target patient population and the expected accrual rate at their own site. Logistically, it may not be sensible to undertake a trial if the site will not be able to accrue a reasonable number of patients. Clinical trial subjects are not reflective of "reality"

  and restrictive eligibility criteria are probably the greatest contributor to poor trial recruitment. Recent surveys have suggested that up to 95% of an otherwise eligible target population is not eligible to participate in industry-sponsored trials.

  A common mistake is to take into consideration the therapeutic indication while failing to adequately consider the exclusion criteria. A patient with angina is not the same as a patient with angina who must be a male age 45-70 with type II diabetes and hypertension. 			

The protocol must clearly state the primary and secondary outcome measures of efficacy, and how these will be evaluated. The primary outcome measure forms the basis for the statistical analysis and sample size calculations. Sample size calculations are based on the variance in an outcome measure and the expected magnitude in differences between treatments. The sample size calculations are often only valid for the primary outcome measure. This in itself is not a major flaw in study design, but from a practical perspective investigators should be aware that more secondary endpoints translates into increased work for the study team. 			

Familiarity with study endpoints and measurements is important. Some investigations may have limited availability or high cost that may limit feasibility of the trial at a site. In some situations, specific training or accreditation needs to be obtained in order to perform the study measurements. The invasiveness of the procedures and convenience for the study participants must also be considered, as this will have great impact on study accrual and compliance. 

The research protocol should always contain a statement of the ethical considerations involved.

Many of the ethical considerations in clinical trials can be resolved if the scientific and medical rationale for the study and the scientific method used to implement the study is sound. An ethical issue previously mentioned is ensuring that an appropriate standard of care is used. Unfortunately, there is an increasing dilemma for trialists as effective treatments exist for an increasing number of medical conditions. For example, rheumatoid arthritis trials frequently require subjects to have failed several disease-modifying therapies, have active disease, but still be on maintenance methotrexate. Despite the presence of active disease, the eligibility criteria may restrict recruitment by imposing additional criteria, e.g., elevated ESR or C-reactive protein, that may not be met due to the methorexate therapy.

With respect to Phase I studies, there is a unique ethical problem. The Declaration of Helsinki states that "medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research."

  In the context of Phase I studies, there is often a very low or even negligible chance of benefit, and patients should be informed of this in the consent document and during the accompanying investigator-patient discussion. This issue is further complicated in the setting of healthy volunteers, where there is no medical benefit and the only incentive might be financial. 

The Declaration of Helsinki states "at the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic, and therapeutic methods identified by the study." Ethically, this is fair, but pragmatically it is often not achievable, and has been an increasingly common problem at our site. For early phase studies there simply may not be enough study drug available to provide ongoing supply, especially in the case of biopharmaceuticals. Furthermore, given that a Phase I study does not establish proof that a treatment is effective, continuing supply of drug should not necessarily be considered in the decision to participate in a study. 

In later stages of development, local considerations often determine the availability of study drug. For example, in Australia there is a variable period between registration and the governmental decision to subsidize the cost of the drug (if at all). During this time, companies may no longer provide study medication free of charge to the study participant. Consequently, study patients may need to stop the drug regardless of its effectiveness, and make alternate arrangements or, in some cases, the hospital drug committee may be morally obliged to cover the drug costs. However, hospitals are increasingly unable to provide such assistance. Investigators should clarify with sponsors the arrangements for ongoing supply of drug prior to participating in a study. 

Trial management consumes vast resources in terms of time, money, and manpower. If a site accrues too many patients or has too many trials, site resources may be stretched too far, compromising both trial quality and patient safety. If only one or two patients are accrued to a trial, it may simply be a waste of resources that could be diverted elsewhere. These difficulties for sites are compounded by irregular volumes of activity and payment schedules geared toward payment at the completion of subject participation. Furthermore, "completion" is defined as that time at which the monitor has visited the site to ensure that all documentation is complete—a somewhat tenuous timeframe that is outside the control of the study site. From our perspective, it is probably safer to aim to have enough studies so that activity is likely to be slightly higher than capacity, rather than to aim to meet capacity and fall short due to underrecruited studies. 			

Factors influencing recruitment include the eligibility criteria of the trial, the availability of the patient population, the expected overall accrual timeline of the trial, and acceptability of the trial to patients. Databases may facilitate assessment of anticipated numbers accruable but these still tend to over-estimate the eligible population. When sites are approached to join a study well after other sites have started accruing, it is a sure sign that it will be difficult to recruit to the study. The referral base is another important factor: surgeons or physicians who will be relied on to refer patients must be aware of the trial and preferably have a track record for referrals rather than just well-meaning enthusiasm. In the situation where there are multiple or external investigators, at least one investigator should take a genuine leadership role to promote recruitment. Trial complexity is a major consideration. Frequent or long visits, or multiple procedures, can be a major disincentive to participation, especially in the case of healthy volunteer studies or for very unwell patients. 

The practical aspects of coordinating the increased demands of clinical trials for a sick patient population also require careful consideration. A recent study of a treatment for motor neuron disease at our site required early morning visits in order to complete the study assessments that were conducted at multiple clinics, and to accommodate the schedule of the busy and limited clinic times. Given the travel difficulties, preparation times, and reliance on carers that is characteristic of this patient population, many of the participants found the visits too onerous and opted to withdraw prematurely. 

Assessing the study coordinator workload associated with a trial is difficult. If possible, it is worthwhile to obtain a copy of the case report form (CRF), as this will indicate the amount of data to be collected and collated. Some trials take a minimalist approach to data collection and are "quick and simple and reliable."

  Most trials, however, examine multiple endpoints, and the data collection requirements are substantial. This is particularly the case for industry-sponsored Phase III studies aimed at drug registration. These trials will increasingly incorporate additional time-consuming data collection including patient diaries, quality of life, economic health assessments, and additional samples for population pharmacokinetics and pharmacogenetics. As trials become global, further logistic considerations include remote randomization and shipping tissue, blood, or imaging to other centers for central processing or independent assessment. As investigators, we tend to forget that each hour of patient contact may generate several more hours of documentation activities for our study coordinators. Finally, and importantly, not to be underestimated is the time spent by study staff with monitors, auditors, and at investigator and initiation meetings. A recent survey reported that a standard oncology trial required approximately 200 hours per subject and that 32% of this time was devoted to nonclinical time.

Funding for a trial should be at least adequate to cover the costs of trial administration, otherwise the center will operate at a loss. Many believe that all of the costs of clinical trials should be remunerated, especially in the case of industry-sponsored trials. A common practice, however, is to reimburse only the trial costs associated with per-protocol procedures that are not part of standard care. This might be acceptable when the site is financially supported by a parent institution, e.g., free use of space in a hospital, but for a fully independent site such trials are financially unsatisfactory. Staff commitments to the project management and trial documentation are a major source of study cost, and are often underrepresented in the budget. Other items that are often neglected in study budgets include the cost of preparing ethics applications and the archiving of data once the study is closed. Itemized budgets should be requested from the sponsor where possible. If the proposed study payment is too low, then submit an itemized budget to the sponsor to clarify and justify the need for an increased budget. 

A major burden in our unit is expanded access schemes or extension studies from previous trials. As indicated previously, these schemes provide the opportunity for ongoing drug availability at the end of a trial. Unfortunately, in our experience, these schemes are remunerated less than the original studies and require as many or sometimes more resources. 

Sponsors often request feasibility assessments well prior to a trial commencing. In our experience, the site is often provided with a very limited description of the protocol, and for confidentiality reasons the name of the study drug is usually withheld. This decreases the ability of the site to provide adequate feedback regarding the protocol, both from the perspective of feasibility (including budgetary estimates), and level of interest. A confidentiality agreement may overcome these problems. If the feasibility review is unsuccessful, feedback from the sponsor should be requested so the relevant issues can be addressed for interactions with future sponsors. 

Protocols are commonly supplied to investigators relatively late in the start-up period of a trial, and the majority of sites will have little input into the protocol. Input from a site is more likely if the trial is early phase. Regardless of this, we believe it is beneficial to provide to the sponsor with some feedback regarding any problems related to a protocol. The benefit of this is that sometimes appropriate amendments can be instituted; in addition, the design of future studies may be improved, as will the timelines for getting important new treatments to patients who need them. 

Given the resources required to establish and maintain a clinical trials unit, the motive for establishing a site should be defined. Reasons may range from enthusiasm for clinical research to purely financial incentives. Our main priorities are serving our academic interests, contributing to improvements in the standard of care of patients, and providing a service to our affiliate institutions. The motivation for establishing a site should be considered when selecting a trial. Otherwise, participation will be a futile and unrewarding experience. 			

The expertise and academic interests of our staff may influence direction of the unit. The identification of areas of therapeutic expertise and establishment of niche specialities, e.g., human experimental models, is an important aspect of developing a research strategy and business plan. Strategic alliances and professional networks help define the nature of the trials the unit adopts. Specific academic partnerships and partnerships with industry can lead to a "pipeline" of trials. While not always relevant to small sites contributing to large studies, it is nonetheless important to ensure that appropriate publication rights are in place, as publications contribute to a track record for the site. 

In this article we have outlined some of the issues that we believe a clinical study site should face when considering whether to undertake a study. Systematic appraisal of the protocol prior to agreeing to participate is an important process to allow problems to be identified, and to ensure that the trial site has made a considered and informed decision to participate. This process is important because overall the clinical research process can be improved by sites taking a proactive role in the design and conduct of clinical trials.  			

1. G.H. Guyatt, "Users' Guides to the Medical Literature [Editorial]," 

2. D. Moher, K.F. Schulz, D.G. Altman, "The CONSORT Statement: Revised Recommendations for Improving the Quality of Reports of Parallel-Group Randomised Trials," 

, 357 (9263) 1191-1194 (April 14, 2001). 

3. D. Moher, C.S. Dulberg, G.A. Wells, "Statistical Power, Sample Size, and Their Reporting in Randomized Controlled Trials," 

4. World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects, sourced online at http://

5. J. Dancey and B. Freidlin, "Targeting Epidermal Growth Factor Receptor—Are We Missing the Mark?," 

6. P. Spira and R. Beran, Australian Gabapentin Chronic Daily Headache Group, "Gabapentin in the Prophylaxis of Chronic Daily Headache. A Randomized, Placebo-Controlled Study," 

The protocol should describe the minimization process and processes to minimize systematic bias, as this can influence practical aspects of the study.

Protocol Appraisal: A Study Site's Viewpoint

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.

 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.

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. 

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: 					

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.

 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.

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.			

 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 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.  

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 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.

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). 

 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. 

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. 			

 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. 

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. 

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. 

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. 

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. 

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

Clinical Trials in CEE: Harnessing the Potential

The EU's newest draft legislation contains GCP rules that somehow aren't already law.

Almost 15 years ago, European Union officials started work on new clinical trials rules that would govern not only on how medicines were to be tested, but also on the requirements for the medicines. This summer, what may be the final elements of the draft legislation appeared at long last?and it covers much more than investigational products. It's taking some time, but inch by inch the EU is getting there.

The new text is a draft European Commission rule "laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of manufacturing or importation of such products."

This is another of the long-awaited pieces of secondary legislation implementing the 2001 clinical trials directive

 and the Council of 4 April 2001. It addresses the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice (GCP) in the conduct of clinical trials on medicinal products for human use.

It will, when finalized, give shape to the directive's requirements which state that principles of GCP and minimum standards shall apply to the authorization of manufacture and import of investigational products. Manufacturing requirements have already been laid down in another piece of secondary EU legislation

 regarding medicinal products and investigational medicinal products for human use.

 But because the general EU rules on authorization of pharmaceuticals (Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use

) does not cover medicines intended for research and development trials, the EU wants to establish minimal requirements to guarantee the quality of investigational products used in clinical trials. So the draft text covers applications for authorizations to manufacture and/or import investigational products, the management of applications, and the granting and the content of the authorizations.


Special provision has been made to ease requirements for noncommercial clinical trials, following intensive lobbying by the nonprofit sector.

 As the new text notes, a trial conducted by researchers without the participation of the pharmaceutical industry "may be of great benefit to the patients concerned." When non-commercial clinical trials are conducted with authorized products and on patients with the same characteristics as those covered by the indication, manufacturing or importation requirements already fulfilled by the authorized products are to be taken into consideration.

Furthermore, EU countries may choose to apply "specific modalities"?Eurospeak, in this case, for a more flexible approach?to these trials even when the patients do not necessarily have the same characteristics, "due to the specific conditions under which non-commercial trials are conducted...in particular as far as the manufacturing or import requirements for authorisation and the documentation to be submitted and archived for the trial master file are concerned." To justify this exception, the text acknowledges that "the conditions under which the non-commercial research is conducted by public researchers and the places where this research takes place make the application of certain of the principles of good clinical practice unnecessary or guaranteed by other means."

There is another area of flexibility, too. The regulatory authorities in the EU "may also take into account the special position of the trials whose planning does not require particular manufacturing or packaging processes." Labeling of investigational medicinal products intended for trials of this nature may be subject to simplified provisions.

The new rule is extensive and detailed. But its essence is that an authorization to manufacture or import investigational products will be required for both total and partial manufacture, and for processes of dividing up, packaging, or presentation?even if the products manufactured are intended for export. Authorization will also be required for imports from non-EU countries. This authorization will not, however, be required where pharmacists in dispensing pharmacies are carrying out the preparation, dividing up, or changing of packaging and presentation solely for retail supply.

The authorization application has to provide details of the product and pharmaceutical forms; the relevant manufacture or import operations and, where relevant, the manufacturing process; the suitability of the premises and equipment at the place of manufacture or import; and staff qualifications. And the nonclinical and clinical information available on an investigational product "shall be adequate to support the proposed clinical trial."


This new piece of draft legislation does more than merely set out product-related rules, however. It insists that trials with investigational products for human use must comply with the international principles and the EU guidelines relating to GCP in their design, conduct, and reporting. It is also the vehicle for detailed EU guidance complementing the outline of the general EU rule on clinical trials

?a sort of mopping-up exercise for a number of areas where industry, the EU, and the clinical trials community had all been looking for clarification. 

The text reiterates many of the familiar concepts underlying GCP-qualified staff, scientifically sound and ethically well-defined trials, quality assurance, data management. And it puts an emphasis on the individual?for instance, "the rights, safety and interests of the trial subjects shall prevail over those of science and society." But it also extends the existing EU legislation on matters ranging from archiving to qualifications of inspectors and inspection procedures.

Regarding ethics committees, for instance, the new text recalls the duty on each committee to adopt rules of procedure to meet the 2001 directive. It requires committees "in every case" to retain the essential documents on each clinical trial for at least three years after its completion. And it obliges regulatory authorities to set up "appropriate and efficient systems" for communication of information with ethics committees.

Similarly, for sponsors, it provides for delegation of "any or all of his trial-related functions to an individual, a company, an institution or an organisation," but makes clear that "the sponsor shall remain responsible for ensuring that the conduct of the trials and the final data generated by those trials" comply with the clinical trials directive. And it adds the clarification that "the investigator and the sponsor may be the same person."

On the investigator's brochure, it demands a presentation which is "concise, simple, objective, balanced and non-promotional," in a form "that enables a clinician or potential investigator to understand it and make an unbiased risk-benefit assessment of the appropriateness of the proposed clinical trial."

Details are also provided on the Trial Master File, defined as the essential documents which enable evaluation of both the conduct of a clinical trial and the quality of the data produced. 

The sponsor and the investigator are required, in every case, to retain the essential documents for at least five years after completion of a trial, "in a way that ensures that they are readily available, upon request, to the competent authorities." Trial subjects' medical files "are to be retained in accordance with national legislation and in accordance with the maximum period of time permitted by the hospital, institution or private practice." 


But perhaps the most extensive complementary regulation relates to the processes of inspection. The nature of some of this draft legislation speaks volumes about some of the difficulties that the pharmaceutical industry and clinical trials professionals have been running into in the past?and fear they may run into even more in the future. Incredible as it may seem, the EU is only now attempting to require that clinical trials inspectors should know anything at all about what they are inspecting!

The section on qualifications of member states' inspectors says that they will have to be suitably qualified and experienced in medicine, pharmacy, pharmacology, toxicology, or other relevant fields, and receive appropriate training within systems that "maintain and improve their skills." 

At the same time, demonstrating how little this has been guaranteed so far, inspectors are to be provided with means of identification, and will have to be "made aware of and maintain confidentiality whenever they gain access to confidential information as a result of good clinical practice inspections." 

Each EU country will have to establish a legal and administrative framework within which its GCP inspections operate, which will define inspectors' powers for entry into clinical trial sites and access to data. And it is the responsibility of each individual state to provide sufficient inspection resources and appoint enough inspectors so that compliance with GCP is adequately checked.

Now, 15 years after the idea was sown, many of the EU's clinical trials rules have been adopted, and some have been implemented. But not all of the necessary legislative texts are in place?as this latest proposal demonstrates. Over the coming months, in the light of comments received on this proposal, EU officials will formalize this text'or something like it. And then there will be a further six months before it comes into effect across the 25 EU member states. So until then, in theory at least, the compliance of clinical trials with GCP could continue to be assessed by national officials with no training, no knowledge of medicine or medicine development, and nothing to stop them telling everyone they know about whatever they found at the latest inspection they carried out.


1.http://pharmacos.eudra.org/F2/pharmacos/news/DirectiveGCP20040614.pdf2. Directive 2001/20/EC of the European Parliament.3. EU Official Journal L 121, 1.5.2001, p. 34.4. Commission Directive 2003/94/EC of 8 October 2003.5. EU Official Journal, L 262, 14.10.2003, p. 22.6. EU Official Journal, 311, 28.11.2003, p. 67.7. P. O'Donnell, "View from Brussels," 

 (April 2004). 8. Directive 2001/20/EC.            

View from Brussels

The EU’s newest draft legislation contains GCP rules that somehow aren’t already law.

The Slow but Steady Pace of EU GCP Rules

FDA encourages clinical data e-submission and boosting development of new therapies to combat bioterrorism, cancer, and obesity. 

Health and Human Services secretary Tommy Thompson is striving to launch a long-term health care information technology strategy before he leaves Washington at the end of the year. The Medicare Modernization Act (MMA) requires the government to establish technical standards for an electronic pharmaceutical prescribing system, and the Food and Drug Administration is pursuing a number of initiatives to support this process. 


At the national Health IT summit in July, FDA acting commissioner Lester Crawford announced a policy that encourages sponsors to file data from drug trials using a standard format, the Study Data Tabulation Model (SDTM), developed by the Clinical Data Interchange Standards Consortium (CDISC). This uniform framework for clinical trial tabulations aims to accelerate clinical research by automating the largely paper-based clinical research process and to more easily integrate data from various sources. 

The SDTM standard is one of several FDA electronic health information initiatives designed to further the shift from paper to e-filings [see sidebar on "Common Language"]. Last December (2003) FDA issued a new rule requiring manufacturers to submit product labeling information electronically when filing new drug applications, supplements, and annual reports. FDA plans to transmit the e-labeling data to the National Library of Medicine, which will make the information available electronically to all users through its DailyMed system. 