Electronic data capture is rapidly being adopted to gather clinical trial data. For example, a recent survey found growing acceptance and use of EDC technology for clinical trials.

 More than 75% of the respondents are involved with more than 10 trials per year-and only one-third of those responding to the survey have yet to use EDC. In addition, a recent analysts' report found that among the top drug companies, web-based EDC technology was ranked the "most important" IT initiative in their drug development programs.

 Despite the numerous articles that have evaluated the return on investment (ROI) for EDC projects from a sponsors point of view, few objective analyses have been performed to evaluate the impact of EDC from a clinical monitor's perspective. Consequently, we conducted a survey to evaluate what clinical monitors think of EDC technology.		

Specifically, the survey was developed to determine the following: monitors' general knowledge of EDC, their experience or knowledge of various platforms, their perceptions of positive or negative characteristics of EDC, their recommendations for EDC providers, and their estimates of the future of implementation of EDC programs in clinical trials.	

We developed an 18-question survey that contained open-ended and forced-choice questions. It was divided into three sections: personal background information, overall knowledge and experience with EDC, and specific characteristics of EDC. Surveys were broadcast faxed to approximately 335 monitors registered with our company; 96 monitors responded within 10 days.								

 The first section of the survey was designed to develop a profile of the responding monitors. The data showed that they were experienced monitors; 63% had more than five years of clinical monitoring experience (Figure 1). They were evenly distributed across the United States. 	

Experience with and knowledge of EDC systems. The second part of the survey addressed the monitors' experience and knowledge of EDC systems. Respondents spontaneously generated the names of 13 EDC companies with which they were familiar (EDC providers sidebar). 			

This section of the survey also sought to gather specific information about respondents' personal experiences with EDC. More than half (54%) of the respondents indicated having direct experience with EDC systems; the majority indicated their experience had occurred during a Phase 3 trial (Figure 2). 			

 Interestingly, respondents were evenly divided on the number of positive and negative comments heard about EDC systems. Half indicated hearing negative things about EDC and half indicated hearing positive comments about their peers' experiences with EDC systems. Respondents were prompted to indicate the positive and negative aspects of their EDC experiences.	

They reported that the best-liked characteristics of EDC were the reduced number of queries and reduced time on site (Figure 3). As a corollary, the majority of monitors indicated that the reduced number of queries allowed them to spend more time with the investigators and staff rather than with reconciling queries. 				

In contrast, the respondents indicated that the aspects of EDC they liked least were the training and the technology support provided by the EDC vendor and the "slowness" of some systems (Figure 4). Follow-up inquiries with the respondents revealed that the slowness they disliked can probably be attributed to the connection speed rather than the actual processing of the EDC systems. 			

 Monitors clearly noted, however, that the support/help desks of many vendors perform at suboptimal levels. They specifically mentioned that it was obvious that a number of help desk operators had no experience in clinical trials and did not understand the difference between a coordinator and a monitor. Furthermore, respondents indicated that numerous issues arose with help desk coverage across time zones, and they encountered pronounced compatibility challenges between some EDC systems and their office computers.	

 The last section of the survey provided some of the most interesting results. For example, 62% of the respondents recommended that EDC vendors provide preprogrammed laptop computers preloaded with EDC software. This recommendation clearly points out some of the early technical challenges monitors have had with systems that were not browser- or thin client- based. (A thin client system is one designed so that most data processing takes place on a server rather than on a desktop computer.)				

Moreover, 24% recommended providing online training for clinical monitors (Figure 5). However, despite some of the challenges of EDC systems, over 70% of clinical monitors rated their experience with them as positive. An even more compelling 96% of clinical monitors would recommend the use of EDC on their next clinical trial (Figure 6).	

Although clinical monitors who responded to our survey reported a number of concerns with EDC providers-specifically, technical compatibility and support-an unprecedented majority of clinical monitors indicated their preference that EDC systems be used. They cited such advantages as a reduced number of queries and reduced time on site. Those advantages are consistent with the claims of EDC providers who cite the systems' potential for increased efficiency and cost savings. 						

We also captured information about monitors' initial thoughts on the future of EDC implementation that suggests that they expect EDC to become a fundamental technology in future clinical trials-but not immediately. Although 68% responded that they do not expect EDC to be used in a majority of clinical trials within the next two years, 81% of the respondents said they expect EDC to be used in a majority of clinical trials in the next five years. As a group, clinical monitors may be among the strongest advocates for adoption and implementation of EDC technology for clinical trials.	

1.	Lisa Roner, "Survey reveals EDC use on the rise for clinical trials," Eye for Pharma, (10 May 2001).				

2.	2001 Drug Development Services Market Survey-Finding Reality Within the Contract Research Marketplace (Bear Stearns & Co., Inc., 383 Madison Ave., New York, NY 10179).	

Rod M. Saponjic*, PhD, MBA, is senior vice president for MonitorForHire.com, 5752 Oberlin Dr., San Diego, CA 92121, (858) 453-8030, fax (858) 453-8040, email: RequestInfo@MonitorForHire.com, 		

. Scott Freedman, MBA, is president or the company; and Ali Sadighian is manager, Clinical Operations.	

*To whom correspondence should be addressed.	

Articles

Feature Article

For years, EDC providers have claimed that the technology can increase efficiency and potential cost savings. Survey results indicate that clinical monitors agree.

What Monitors Think of EDC

Pharmaceutical companies and contract research organizations are setting up an increasing number of clinical trials in Central and Eastern Europe. The region offers attractive opportunities for sponsors to accelerate subject recruitment and to carry out clinical trials according to harmonized international standards and regulations. Recent concerns about data quality and cost-efficiency at CEE investigational sites, however, have led to regular evaluation of sites' clinical research performance and capacity. Now it is essential to introduce benchmarking and performance measurement to the conduct of clinical trials to identify best practices and to continually improve clinical research.	

Several factors have contributed to a significant increase in the number of clinical trials conducted in Central and Eastern Europe (CEE) over the past few years.	

Investigators are well educated, experienced, and highly motivated physicians eager to conduct clinical research-and thus have opportunities for professional development, international networking, and publication. 

CEE nations offer a huge pool of easily reachable patients interested in participating in clinical studies because of free access to modern therapies and medical equipment.

Overall trial costs are lower than those in Western Europe.

For the most part, well-defined regulatory processes make it possible to obtain all of the necessary approvals in a relatively short time. 

In the highly competitive clinical research environment, however, the key issue for CEE is how to respond to new challenges and how to stay competitive. This could be achieved by overcoming the logistical and cultural hurdles, which are still considered a major concern by potential sponsors, and by comprehensive building of expertise and competencies that will provide a strong platform for future expansion of CEE studies.			

The most appropriate response to the first suggestion would be creating a win-win situation for all parties involved in clinical research. This implies sustainable support and willingness of the sponsors to allocate resources for adapting necessary site infrastructure-and also extra effort by CEE governments to encourage new types of investments. That effort could mean technological restructuring of the health sector and creating opportunities for highly trained health professionals, investigators, and site personnel to acquire new practices and knowledge by participating in multinational research.	

The second suggestion refers to building Centers of Excellence-institutions dedicated to performing exceptional clinical research in an environment focused on raising the overall standards of quality and effectiveness in various health care areas. Those centers could be defined and subsequently selected based on specific criteria, such as clinical research experience, facility description, investigator and research staff experience and expertise, and potential subject demographics/base. Centers of Excellence are meant to be core sites in CEE for developing expertise and capabilities for clinical research. Their main objective is to continually do more with less without compromising quality.	

The presentation of a respective site or country can be judged only in comparison with other sites or countries participating in the same clinical trial. Applying performance benchmarking as a standard competitive tool-a tool focused on a set of compatible and comparable key performance indicators-could make the decision process transparent, effective, and more objective.	

An additional goal is to enable sponsors to improve the quality of clinical research by using the results to compare the performance of investigative sites. Benchmarking could, therefore, be recognized as an essential technique for achieving continuous improvement.	

Here we present the results of a performance benchmarking analysis that was carried out recently on a few international, multicenter clinical trials sponsored by Novo Nordisk A/S in various European countries. To reveal critical measures that change behaviors and drive performance, we measured performance indicators related to speed, quality, and quantity in clinical research aimed to reveal critical measures that change behaviors and drive performance. 							

The primary short-term objectives of this study were to identify the best performers across the region and to identify the aspects of conducting a clinical trial that could realize the most benefit from process improvement. Our long-term objective is to create a competitive environment in which it is possible to obtain full understanding of the performance and enablers of a "best in class" knowledge management process.	

We currently perform regular benchmark reports following each core clinical trial that involves site participation in different countries worldwide. Here we present key findings from a benchmarking report that involves 11 countries, 5 from Central and Eastern Europe and 6 from Western Europe. 	

 We defined a set of key performance indicators aimed at measuring the performance of various parties involved in different phases of clinical trial management-sponsor, health authorities, ethics committees, and investigational sites. We expressed the indicators as number of days from protocol review committee approval to health authority (HA) approval, from HA approval to first subject first visit (FSFV), and from FSFV to last subject first visit (LSFV), with the following results.				

The shortest time for HA approval was 61 days in Spain.

The longest time for HA approval was 162 days in Greece; however, Greece recruited its first subject 9 days after obtaining HA approval.

Portugal recruited its first subject 137 days after obtaining HA approval.

France had the shortest recruitment time, 17 days.

Poland registered the longest recruitment time, 218 days.

A detailed overview of all participating countries is shown in Figure 1.	

We concluded that the average time to get regulatory approval was about the same in CEE countries (126 days) as in Western Europe (121 days). The average time from HA approval to FSFV was shorter in CEE countries (38 days) than in Western Europe (68 days). The average recruitment period in CEE countries was 183 days (range 157-218 days). Although recruitment in Western Europe averaged only 129 days (range 17-175 days), sites in CEE countries randomized substantially more subjects.	

Quantity was measured in terms of number of subjects randomized during the original recruitment period and when the recruitment period was complete. The trial's target enrollment for this trial was 455. Only 260 subjects were randomized during the primary recruitment period-and only Croatia, the Czech Republic, and the Russian Federation reached or exceeded their targets. At the end of the extended recruitment period, an additional 81 subjects were randomized, but the recruitment target of 455 subjects was not met. Only 341 subjects of the planned 455 (75%) were finally randomized. Nevertheless, all of the CEE sites recruited more subjects than originally planned (Figure 2).				

Quality of the data was the last, but not least, part of the benchmarking report. We measured data quality in terms of the number of substantial queries issued per case report form (CRF). In that respect, sites in CEE countries were the best performers, with substantially fewer queries than sites in Western European countries (Figure 3).	

It is important to stress that the results presented from this particular trial are very much in line with the outcomes of other benchmarking reports prepared so far.	

We find benchmarking to be a cost-effective way to introduce best practices to the clinical development process. Transforming performance through benchmarking reveals how developing and implementing an effective metrics program can lead to improved data quality, reduced time to market, and lower overall development costs.				

Using metrics to compare speed, quantity, and data quality demonstrates that CEE countries offer regulatory, sponsor, and investigator performance in clinical research that is good overall-and in some cases even better than their Western European counterparts. Additional studies should be performed worldwide to create new levels of clinical benchmarking and to facilitate clinical analysis across thousand of subjects. But on the basis of the analysis reported here, CEE countries offer competitive and attractive locations for investing in future clinical research.	

1.	P. Meng, "Eastern promise," Good Clinical Practice Journal, 4 (1) 8-11 (1997).				

2.	IBC Conference on Clinical Trials in the Central and Eastern European Countries, Budapest, September 1998.	

3.	Centre for Medicines Research International, "Benefits from benchmarking drug development," RQD Briefing, 1998, cmr.org. 	

4.	Continuing Medical Education Conference on Benchmarking and Performance Measurement in Clinical Trials, London, January 1999. 	

5.	Scott Martin and Falan Austin, "Getting the measure of performance in clinical research," Good Clinical Practice Journal, 9 (12) 19-22 (2002). 	

6.	9th Applied Clinical Trials European Summit, Interactive Focus Session: Latest experiences in Central and Eastern Europe, Lyon, France, April 2002.	

Dražen BabicÂ´,* MD, MSc, is a regional medical director of Novo Nordisk A/S Regional Office South East Europe, Železna cesta 18, 1000 Ljubljana, Slovenia, +386 1 2342 300, fax +386 1 2308 362, email: 		

;  Iva Kucčerova, MD, is a regional trial manager of Novo Nordisk A/S International Operations.	

Pharmaceutical companies and contract research organizations are setting up an increasing number of clinical trials in Central and Eastern Europe. The region offers attractive opportunities for sponsors to accelerate subject recruitment and to carry out clinical trials according to harmonized international standards and regulations. Recent concerns about data quality and cost-efficiency at CEE investigational sites, however, have led to regular evaluation of sites' clinical research performance and capacity. Now it is essential to introduce benchmarking and performance measurement to the conduct of clinical trials to identify best practices and to continually improve clinical research.

Benchmarking Clinical Trials Practices in Central and Eastern Europe

"Full disclosure is a necessary precondition to free choice. Accordingly, subjects who do not understand the potential risks of a trial cannot be said to have chosen freely to face those risks."		

TABLE 1  Problems with content and readability			

There continues to be much interest in informed consent, both its theoretical underpinnings and its practical applications. As clinical auditors who have reviewed hundreds of consents at clinical research sites and asked staff members about their consenting procedures, we observe, first-hand, some of the practical applications of sponsor, CRO, and investigator attempts to adhere to good clinical practice standards and guidelines for informed consents. Despite widespread attention to tightening this component of clinical research, there remains much room for improvement.	

Federal regulation and industry standards regarding informed consent have shifted progressively over time. Kiev, in a comprehensive review of the informed consent doctrine and its application to clinical research, discusses the evolution of case and administrative law leading to greater patient self-determination and rational decision-making.

 It is now expected that potential subjects be provided with disclosure of facts, probabilities, and opinions material to their making an intelligent choice or decision about participating in a clinical study. Some recent civil cases, in which investigator conflict of interest and breach of fiduciary duty resulted in a failure to disclose an important material fact, have resulted in the necessity for even more disclosure of information.	

 Interest in improving the readability of informed consents is growing. Zanecchia

 examined readability issues and devised strategies to make consents more comprehensible. In general, these strategies aim at simplification, completeness, and improved visual appeal.	

 reviewed 12 randomly selected consent forms submitted to a hospital institutional review board. He determined that they were difficult to read. They had too many uncommon words, too many words per sentence, and sometimes failed to meet good document design principles. In 1998 the National Cancer Institute published guidelines that would facilitate development of easy-to-read consent forms.

 As Hochhauser, who used these guidelines in his analyses, points out, "Word familiarity has been shown to be a major factor in a reader's ability to understand written materials. Prospective participants have a hard time understanding not only words but basic clinical research concepts as well."		

TABLE 2  Problems with consent process			

Lin and a team of reviewers assessed consent forms for 71 studies conducted in Taiwan.

 The four most frequent deficiencies, those that occurred in 50% or more of the consents, were the following missing items:	

Worldwide regulatory status of the investigational drug

Person to contact about the trial or in case of emergency

Common side effects of the investigational drug and their frequency of occurrence

Trial treatments and probability for random assignment to each treatment.

Lin and the team concluded, however, that the consent forms they reviewed did, in general, comply with international guidelines.	

Previous research also stresses the subtle nature of the consent transaction. Mackintosh and Molloy suggested a simple improvement to the introduction of the consent form that establishes rapport with the reader.

 Sharp suggested improving the process of obtaining consent by including better, more skillful oral communication.

 Getz, in a recent online survey of subjects who completed a clinical study, found that in one in seven cases subjects stated that no one on the study staff reviewed the consent form with them, and a high percentage said that they did not know what questions to ask.

Here, our purpose is to identify continuing problems in the delivery of study consent and to discuss reasons that these issues plague the pharmaceutical, biotech, and device industries.	

We apply three standards to this discussion. The least burdensome, as seen in the figure, are the FDA regulations specified in the Code of Federal Regulations and in guidance manuals. The next highest hurdle is represented by the ICH Guideline for Good Clinical Practice (4.3.3 and 4.8.10). The highest standard is in current thinking on the subject by industry, academia, and regulatory agencies. This standard is gleaned from recently published papers and from discussions with thought leaders. We apply all these standards, for which there is considerable overlap, to the discussion that follows.	

First, we identify problems with content and readability. These issues include informed consent design and layout; next, problems with the process of consenting subjects; then possible reasons that these sets of problems occur. Finally, we examine ways in which sponsors can prevent these problems.	

Table 1 displays frequently encountered problems with the content and readability of informed consents. The problems listed are from consents we examined that had been approved by IRBs and reviewed by sponsors and clinical department staff members. Below we highlight a few of the more significant problems in the tables.		

Three levels of standards that apply to informed consent process, according to current industry and academic thinking.						

 Despite being widely circulated in 1997, the ICH recommendation that the investigator inform a subject's primary care physician about enrollment in a study is rarely implemented (ICH Guideline for GCP, 4.3.3). As yet, we have not seen that mentioned in a consent form. Subjects sometimes fail to mention critical clinical information about their medical histories that would preclude enrollment. Thus, a subject's primary care physician might, in certain instances, warn the principal investigator about these conditions, thereby preventing a dangerous situation and nonevaluability.	

 The study drug or the study's procedures could injure a subject. A mechanism should be in place to pay for treatment of medical injury. Often this mechanism is not fully described and has contradictory information that is confounded by discussion of the subject's health insurance.	

 Despite strong statements about birth control and pregnancy in study protocols, consent forms do not have sufficient warnings regarding pregnancy, requirements for pregnancy tests and birth control, and obligations should conception occur while on study. Given liability issues surrounding this topic, one would think that sponsors would insist on strong language in consents.	

 The 2000 Declaration of Helsinki questioned the ethics of conducting placebo-controlled studies when an approved treatment exists. Yet placebo-controlled trials remain prevalent. It is, therefore, critical that subjects understand their chances of receiving a placebo and what can happen if they go undiagnosed or untreated. It is also important to understand what the alternatives are to enrolling in the study, especially if there is an approved treatment not offered as an arm in the study.	

 A consent form is a kind of contract. Both parties to the agreement have obligations. Subjects must recognize that they have an obligation to inform study staff about their clinical conditions even if an abnormality seemingly has little to do with the study.	

 Text that is too dense or is poorly displayed is intimidating and hinders comprehension. Simplifying, assisting in the flow of ideas, and avoiding confusion is an instructional design task requiring writing and layout skill and experience.	

Table 2 displays problems found in the process of obtaining consent from potential study subjects. Some of the more frequently encountered deficiencies follow.				

 Sites sometimes use a copy of the case report form (CRF) inclusion/exclusion criteria as a source document to support a subject's eligibility and enrollment in a study. Instead, entry notes should be made in the subject's medical record. The time consent was obtained should be included to indicate that no study-specific tests or procedures were performed before obtaining informed consent.	

 A serious deficiency we encounter is when consent is obtained by a person who lacks sufficient clinical background to adequately explain the study requirements and answer questions. Complicated studies require substantial physician involvement.	

 Numerous problems emerge with special consent procedures, such as when the next of kin or a legal guardian signs the consent form. If an individual has legal medical power-of-attorney, that fact should be noted on the consent form. When a next of kin signs for a subject, the individual's relationship to the subject should also be indicated on the form. We often find that a spouse has signed on the subject signature line; but, because spouses who sign are not subjects, they should sign as the spouse on a different line. When no emergency situation exists, then only the person with legal signatory authority should sign for a subject.	

 Study candidates sometimes are given multiple consent forms to read and sign just before a procedure such as cardiac catheterization. Some investigators say they do this because they are not sure for which study the candidates may qualify until after the procedure. Therefore, signing multiple consents is an "insurance policy" for the investigator. Study candidates cannot be expected to give truly informed consent under such high-pressure circumstances. 	

 As mentioned earlier, we examined content problems in consent forms that had been approved by IRBs. Study staff members often expect that an IRB-approved consent form is "perfect"-that it has no deficiencies. This is a false sense of assurance. IRBs frequently approve defective and suboptimal consent forms. It is the investigator's responsibility to obtain GCP-compliant consent.				

Furthermore, we encounter IRBs and academic institutions  that have outdated ideas and rules about what should and should not be written in consent forms. Some do not allow the listing of an IRB contact person. On the other hand, many central and national IRBs sometimes fail to sufficiently scrutinize consent forms for content, which can result in the omission of important information. Many IRB members, regardless of the type of IRB, do not devote sufficient time to reviewing and discussing critical consent content.	

 Sponsors and institutions, particularly hospitals, are sometimes reluctant to take on additional liability for medical injury resulting from study drugs and procedures. The reluctance and efforts at "held harmless" clauses in contractual agreements lead to compensation for injury sections that are full of obfuscation and contradictory statements.	

 Consent forms are rarely proofread sufficiently. For example, we recently encountered an IRB-approved form in which the confidentiality section read, "Should the results of the study be published in the medical literature or presented at scientific meetings, you will be identified either by name or any other manner." It appears that none of the 18 subjects enrolled at the site that used this consent form carefully read this section either.	

 The consent process can break down because it is sometimes a piecemeal process, spread out over several encounters between the patient and the care provider-and may involve more than one member of the study staff. Sometimes it's half subject recruiting-persuading a patient to sign up-and half going over the particulars of the study to obtain consent. In many cases, the physician performs the recruiting part, then a study nurse or coordinator discusses the fine points of the consent form with the subject.	

 The consent process is sometimes rushed, particularly when it occurs on the same day as surgery. We have encountered circumstances in which study subjects signed four different consents for four different studies just before cardiac surgery. Study mills sometimes conduct the consent process in waiting rooms. We once reviewed a medical record that documented that the subject was inebriated when he signed the consent.	

 Sometimes an unqualified and/or untrained person, such as an investigator's secretary, conducts the consent process. For a very complex study, even delegating the consent process to a registered nurse is unacceptable. A medical assistant may, however, assist the investigator in obtaining consent for a simple two-week allergy study. That is, the qualifications of the person administering the consent process should match the clinical complexity of the study design, procedures, and risks.	

Failure to understand relevant state legislation.

 Staff members who obtain consent from members of vulnerable populations, particularly minors and the aged, should be knowledgeable about state laws regulating assent and medical power-of-attorney. We have discovered too many instances in which the adult who signed for a minor was not that child's legal guardian and in which the person who signed the consent did not have medical power-of-attorney for the enrolled subject.	

The consent process for clinical studies mirrors the consent process for hospital admissions and for elective surgery. The forms have too much fine print, "legalese," and obscure terminology. Subjects have numerous other concerns on their minds when they are asked to consent to enrollment in a clinical trial. Not all fear can be relieved-but improving the consent process can help alleviate some of a subject's understandable anxiety associated with impending medical tests and procedures.				

Opportunities abound for improving the clinical trial consent processes and the content of the consent forms. Subjects must be given sufficient time to read and digest the information-and they need the time, opportunity, and encouragement to ask questions. As the process nears completion and the time for signatures approaches, site staff members can ask potential enrollees about their comprehension of study processes and risks and probe for unspoken reluctance and uncertainty about specific aspects of a study.	

1.	Donna Shalala, "Protecting Research Subjects-What Must Be Done," New England Journal of Medicine 343 (11) 808–810, 2000.				

2.	Ari Kiev, "A History of Informed Consent Doctrine," Applied Clinical Trials, May 1993, 56–69.	

3.	Denise Zanecchia, "Writing Readable Informed Consent Forms," Applied Clinical Trials, September 1992, 52–62.	

4.	Mark Hochhauser, "Writing, Reading, and Understanding Research Consent Forms," Applied Clinical Trials, May 1997, 66–73.	

5.	Mark Hochhauser, "The Informed Consent Form: Document Development and Evaluation." Drug Information Journal, 34 (4) 1309–1317, 2000.	

Improving the informed consent process and consent forms can not only help subjects better understand clinical research but also reduce the number of invalid consents obtained.

Opportunities to Improve Informed Consent

Recent relative calm on the research scandal front has resulted in diminishing public focus on clinical research oversight and enforcement. The change is visible in a proposed guidance on Financial Relationships and Interests in Research Involving Human Subjects.

 The guidance offers suggestions that research organizations identify and manage financial conflicts of interest, but fails to provide specific standards or requirements or to respond to calls for clear national guidelines.

The guidance applies to all research funded by the Department of Health and Human Services (HHS) or regulated by the Food and Drug Administration. It does not change current FDA requirements that sponsors document and disclose the financial interests of investigators. And it fails to reconcile confusing differences between HHS and FDA policies. Existing guidelines require that researchers funded by the National Institutes of Health (NIH) disclose financial interests over $10,000, while FDA requires that sponsors report financial arrangements with investigators over $25,000. 

Instead, the draft guidance lists points that research organizations, IRBs, and investigators should consider when evaluating whether specific financial relationships create financial interests in research studies that may adversely affect the rights and welfare of subjects. Points to consider include:


	whether a financial relationship makes it inappropriate for an institution to conduct certain research.

	whether a conflict of interest (COI) can be managed by reducing the financial interest, disclosing the interest to prospective subjects, increasing oversight, or modifying the roles of particular researchers.

	the need for research organizations to establish COI committees to address financial interests.

	whether IRBs are following procedures to fully consider financial interests.

	whether to include information on financial interests in consent documents or to modify the consent process to reduce potential bias.

The advisory nature of the proposal aims to appease the academic research community, which objected strenuously to a draft interim guidance on managing COIs issued by the HHS Office of Human Research Protections (OHRP) in January 2001. Research organizations regarded that approach to addressing COIs as overly prescriptive and premature, while patient advocates protested that it did not go far enough to protect research participants. 

Interested parties disputed whether IRBs were too overburdened to deal with financial conflicts, and asked if institutional COI committees were too biased. There was little agreement about what constituted a significant financial interest, who should review COI reports, whether reporting and disclosure should be mandatory, whether financial interests should be banned outright, and whether financial interests should be disclosed to potential research participants during the informed consent process.

The new draft guidance document fails to resolve these issues. It basically leaves it to research entities to determine whether a financial interest could affect research participants and, if so, how best to manage or eliminate it. FDA is accepting comments on the policy through 30 May 2003 and will review these opinions with OHRP and other HHS officials when crafting a final guidance.


Although the draft guidance does not alter FDA policies for reporting financial interests in new drug applications (NDAs), it reflects a change in the agencys approach to monitoring clinical research. FDA traditionally has reviewed selected clinical study reports filed with NDAs to verify the quality and integrity of study data. In the wake of scandals involving harm to trial participants in recent years, the agency increasingly is using its oversight authority to protect study participants. This has involved more audits of IRBs and of clinical sites while trials are going on, instead of just examining research reports and visiting sites later to ensure that investigators followed protocols and consent procedures.

Consequently, FDA BIMO (bioresearch monitoring) inspectors now are reviewing more IRBs and clinical sites in real time. The Division of Scientific Investigations (DSI) in the Center for Drug Evaluation and Research (CDER) is visiting about 150 IRBs each year, primarily those actively overseeing studies under investigational new drug applications. 

Similarly, the Division of Bioresearch Monitoring in the Center for Devices and Radiological Health (CDRH) reviews about 100 IRBs annually to ensure appropriate oversight of studies for medical devices. CDRH also is auditing more trial sponsors to see that they are taking proper steps to monitor researchers and ensure the validity of data.

View from Washington

HHS offers IRBs, institutions, and investigators points to consider when dealing with financial relationships and conflicts of interest in clinical research.

Subject Protection is Goal of Draft Guidance on Conflicts of Interest

When new products come to life in the postmarketing period a significant and growing amount of clinical research continues to be performed on a drug or device. Indeed recently published information indicates such research volume is rising more rapidly than preapproval research, albeit from a much smaller base.1 This trend is all to the goodmuch important information about therapies and diseases can be found by increasing postmarketing research among patients in real-life settings, which cannot be accomplished by the inherent scientific constraints imposed on investigational trials.

Sponsors are increasingly realizing, however, that more rigor needs to be applied to postapproval researchnot that there are issues with subject safety, but rather that poor clinical operations process in postmarketing trials means inefficiency and lost opportunity. 

For many reasons, postmarketing studies are conducted differently than investigational research. Regulations are fewer or nonexistent in some circumstances. Research performed under full good clinical practice is very costly. And, by definition, once the therapy has passed regulatory muster, the safety and efficacy have already been proven through the exemplary rigor the industry follows. Much postapproval research is initiated and performed by individual investigators (in so-called IITs), who simply have an interest in pursuing a personal hypothesis, or who want to keep track of patient experience in a manner more organized than is possible in a regular medical practice. Given such circumstances, it is natural for sponsors to take a pragmatic approach to research after a therapy has come to life.

The incidence of postapproval research is particularly high among medical device companies, where many new products receive approval as variants of existing devices, and thus are not required to undergo long and complex investigational trials. In these circumstances, rigor in following an approved device seems unnecessary and unproductive to many device companies. It is also true that for drug companies, which are large enough to have dedicated postmarketing or Phase 4 units, physical or organizational separation from the investigational side of the company can lead to a philosophical and tactical separation as well.


When it is suggested that postmarketing units are not rigorous enough, those units often (naturally) react with great defensiveness. But in doing so they are missing the pointit is not a question of patient safety or regulatory compliance, its a process problem. Its a business problem.

Reduced rigor in postmarketing trials runs up against two imperatives. One is increasing regulatory attention, the other is integratability of all sponsored research. Regulators are increasingly asking sponsors to follow their drugs in a systematic manner postapproval, and as has been famously publicized recently in the 

, many of these studies are long delayed. Some of these studies have been a condition of the FDAs approval of the drug or device. These studies are delayed or incomplete for many reasons, in part because of the inherent difficulties in conducting research in the live world, but also because the units charged with conducting this research are not used to operating under investigational research standards.

The internally-driven imperative for more rigor in postapproval studies is more widespread. Increasingly, sponsors seek to combine the data, the processes, or the enabling operational technologies (or all three), of both investigational and postmarketing trials. There are several drivers for this. One is the desire to use outside operational assistance (such as that provided by CROs) more judiciously; one way to achieve that is to leverage internal investigational and postmarketing resources to help even out each others workload. Another similar driver is the desire to leverage the significant investment companies have made in clinical trial software systems; in doing so they find they need to align processes, or they risk confusion and poor control. But the key driver in tearing down the wall between pre- and postapproval research processes is to be able to integrate these two rich data sources. 

If an IIT, a registry, or Phase 4 subject experience trial reveals something exciting from a therapeutic or competitive standpoint, it is enormously more cost- and time-efficient for a sponsor to be able to use that data directly, and not have to run a good process trial from scratch to reproduce the findings. Sponsors cannot predict when they may want to use postmarketing data for a label extension, secondary indication, or competitive claims. When the opportunity strikes, data units in postmarketing organizations have to scramble to apply rigor retrospectivelysomething notoriously difficult to do.

The worst thing about a sponsor having two different perceptions of clinical data (pre- and postapproval) is that it creates two groups of staff and two process universes that are incompatible. The skill sets and processes, and therefore the people themselves, are not fungible or shareable. The separate creation of SOPs, training programs, parallel networks of trial monitors, and incompatible overlapping data systems, is highly inefficient.


 I contend that sponsors have nothing to lose and everything to gain by doing all trials to the highest reasonable standards the first time. Rigor might seem more costly, but it is a lot like qualityquality does not cost money, it saves money. The cost of rigor in postmarketing trials cannot compare to the cost of rerunning a trial under stricter standards or of trying to clean a trial retrospectively. The cost of rigor cannot compare to that of losing out on a label extension or to a competitive claim. Neither can the cost of rigor compare to the cost of asking an unprepared staff in crisis mode to help with a regulated trial using procedures with which they are unfamiliar.

The irony is that what we are talking about here is mostly just good clinical practice, something every sponsor knows well. Postmarketing units need to learn more from their premarketing peers. (And while they are talking with each other, maybe investigational trial units can learn from the innovative trial design and technologies which are often first used in the postmarketing environment.)

Technology also helps. If applied properly the evermore ubiquitous electronic clinical trial tools can help enable rigorous processes. And those tools can make it easier for smaller postmarketing research staffs to do more with less. Equally exciting are electronic tools which enable researchers to reach out into patients daily lifeelectronic subject diaries and similar toolsso that the experience of patients outside of the clinic, or outside the artificial constraints created by preapproval trials, can be recorded and analyzed for insights into how to make a good product better, or how to take an alternate tack in a therapeutic strategy.


Of course, not all trials postapproval need be run with investigational rigor. By the very nature of the free enterprise of science many of them could not be run with investigational rigor even if you wanted to do so. Marketing trials can be useful in building provider relationships and in enabling small research that would never otherwise be funded. And some research, like long-running registries, can only be cost-effective if managed in a lean manner. In all these cases, some research is better than none. With minimum safety and compliance standards met, the only thing being compromised in such examples is the potential scientific value, or perhaps the integratability of the data.

But sponsors are recognizing they need to be more careful about this, and err on the side of rigor rather than laissez-faire. The cost of doing small research that is not reusable, or that interferes with the development of an efficient postapproval safety profile, is too high. If necessary, build a wall between those who work under preapproval regulatory requirements and those who support investigator-initiated trials or patient registries. Recognize that these resources will not be fungible. Recognize that the data will not be easily merged, if at all. Recognize all this, and plan accordingly. When there is a hint of wider use of the research results, move it quickly back over the wall to the side of rigor.

Take a long look at how you handle your postmarketing trials. Better processes may be more cost-effective. Better science may breathe new energy into those products of yours that have come to life. 


1. CenterWatch Editorial, Clinical Grants Market Decelerates, CenterWatch 1 (April 2003).            

Process Improvement

Postmarketing research is conducted differently than preapproval research, but data gained using different standards can be difficult to integrate.

Rigor Vivus

There are still major differences in the way ethics committees across Europe deal with assessment of clinical trial protocolsvariations related to the country, and even to where they are located within individual countries. This is the principal conclusion of a newly completed study conducted by a Spanish researcher into how far harmonization has reached into the diversity of clinical trials regulation in the European Union.

The studya PhD thesis at Valencia University by Javier Revuelta, who works in Spain for Merck & Cosets out where the attempts to offer a level European playing field for clinical trials have worked, and where they have not. Revuelta has provided his findings exclusively to ACTs View from Brussels, and told this columnist why he started the study, and what he concludes from it.

His thesis examines in some detail compliance in Europe with the good clinical practice (GCP) norms from the International Conference on Harmonisation (ICH). His work is based principally on data from 1999, obtained from nearly half the ethics committees in Denmark, Germany, and Spain.


Among his key findings are that differences in the conduct of ethics committees correspond closely to the different approaches taken by officialdom across the countries that make up the EU. It is the bureaucracy of each country which influences the manner in which ethics committees operate, he says.

Fifty-eight percent of the ethics committees in the sample studied in Germany, Denmark, and Spain were working in 1999 without having fully adjusted to the operating procedures in the ICH recommendations for GCP, he reports. The great diversity of perimeters defining European ethics committees confirms that they have not achieved the level of harmonization required to evaluate trials conducted at an international level. The start-up of trials in Europe is frequently held up unnecessarily by excessive bureaucratic delay in the ethics committees evaluation.

More to the point, he predicts, there will be real problems in ensuring that ethics committees will be able to adapt to the EU rules to evaluate trial protocols in the time required and according to the new rules, and to follow them up. National and local influences need to change. Germany showed no improvement in common approach in the study that Revuelta conductedvariations and divergences predominated. In Denmark, the data revealed likely problems in providing for evaluation of trial centers and follow-up. Spanish committees are too slowand there are too many of them.


Some of the detailed findings show wide disparities. Committees in Spain urged the sponsors to provide further information on the results on 39 occasionsagainst six times in Germany. Similarly, Spanish committees urged the inclusion of more information on the development of the study on seven occasionswhile no German committee did.

The findings also reveal wide differences in the way that committees behave if they are regional or linked to the trial center, if they are hospital-based or linked to small clinics, university-based or linked to groups of doctors, and so on.

From his own point of view as a clinical trials professional, Revuelta says that what struck him most forcefully in his own research is the general absence of professionalism in document management revealed among almost all ethics committees. This compromises their ability to ensure the protection of subjects enrolled in trials and the scientific validity of the findings, he claims. 


Revuelta also remarks on what he terms the excessive review of the scientific aspects of protocols. Many ethics committees are focusing on this, which implies repetition of work already being done by other committees and by the regulatory authorities, he chargesadding that this generates delays in getting a decision. At the same time, ethics committees dont look closely enough at the local aspects of the protocol. They dont check the suitability of particular studies in relation to the trial centers they are going to be conducted in. Study design is fundamental, but an ethics committee should verify the suitability of the study in the conditions in which it is going to be carried out, he says. Ethics committees were also slack in following up incidents during trials, in assessing the way trials are conducted by investigators, and in checking on the results. 

In his opinion, it has taken a long time for local ethics committees to take on board the idea of European harmonizationlargely because they are made up of local people. Representatives of each country, with its own culture, language, religion, investigational methods, health system . . . werein some casesjust starting to hear in 1998 about international recommendations that had come into force a year earlier. And they are still subject to national or local legislation, with its own administrative and bureaucratic characteristics, while they are evaluating the ethics and the suitability of a protocol which is also being evaluated by another ethics committee thousands of kilometers away.

His study also looks ahead to what the prospects are for improved and more harmonized performance after full implementation of the EU directive on clinical trials (2001/20/EC). This sets out conditions and timing for member states to establish a system for coordinating the work of ethics committees in terms of making them more agilewhich is currently a major challenge, he insists.

Given that the ICH recommendations still have no legal force, the average level of ethics committee compliance with them is just about satisfactorybut there are key areas where implementing the EU directive are likely to prove difficult, he says. 

He highlights as particularly important the evaluation of the suitability of trial sitesin terms of the physical conditions, and the quality of the investigating team, their availability, their resources, and their experience, particularly in relation to the local incidence of the pathology under study. He also focuses on setting up an adequate system for monitoring and control of trials after they have started. And he sees big difficulties in ensuring that the new EU rules will be implemented in a way that will bring about protocol evaluations that are both well-judged and rapid.


After having worked for some time in areas that were linked to European Union affairs, he was already conscious of what he terms the European adventurethe development of harmonized approaches, and the implementation of rules that apply right across Europe. Then, when he started to work in clinical trials, and saw how complicated the authorization process was, he became fascinated by the role of clinical investigation ethics committees. What struck him particularly was that they are referred to in all the international recommendations, and everyone who works in clinical trials, anywhere in the world, talks about them as if they are the same everywherein the face of the evidence that, clearly, they are not. 

It seemed odd to me that in a country as small as Belgium there should be more ethics committees than in France and Germany put together. Above all it wasand isvery strange that the same protocol can be rejected or approved according to which committee does the evaluation. Even more to the point, the reasons for rejection are so often completely different among committees that have turned down a study (without even mentioning the time they take).

So Revuelta started asking himself: Are ethics committees the same in different countries? How do they differ? Do they have the same duties? Logic, and my own knowledge of various countries, suggested to me that there had to be significant differences, he told View from Brussels.

His starting point was that in its clinical investigation, when a multinational company is working in different countries to conduct trials, it agrees on international norms or recommendations, a protocol, standardized internal working procedures, and a single working languageinvariably English. But then there are a series of national particularities that make it obvious that harmonization is still something for the future, and that at present (and even more in 1998, when I started my study) it simply does not exist.

This was what led him to decide that ethics committees would be an excellent index to measure the extent to which good clinical practice harmonization had been achieved across countries.These committees were like a thermometer of the temperature of harmonization in each country and each region, he says, because they are the point at which all the aspects converge, making them into individual observatories of how far common methods exist.


What he was looking for was specific data from different countries to check his own concerns about how closely the impending EU rules would be met over the coming years. He suspected that when the objectives and timetable for harmonization were being setthere were failings or a lack of planning among the authorities at international, European, and national levels. Have they been realistic in what they were setting out to do? he wondered.

His conclusion is, pretty clearly, that they have not.

At the heart of the problem is the question of 

. There are no systems in place for monitoring the functioning of ethics committees. Who guarantees that they are operating correctly? he asks. And he lists his own remedies. EU member states should set up national systems, to ensure effective protection of the population, correct scientific review, and administrative flexibility that would assist the development of clinical investigation in the countries of Europe, he urges.

In addition, each member state should establish a national network of what he calls reference ethics committees. There should be fewer than 10 per country (often as few as 5) with, if necessary, a system of rotation. They would be responsible for the scientific and ethical assessment of studies, and for supervising the information coming from local committees. The local committees would be responsible for checking the suitability of trial sites before studies start, and for follow-up during the course of trials, and they would pass their information up to the reference committees.

National health authorities would be responsible for coordinating the establishment and accreditation of the committees, and for ensuring effective communication between them. But the European Union should set up a simple mechanism for inspections and hearings to assess the ethics committees themselves, to ensure their compliance with clear guidelines for them to follow. This, he says, would be something that could really contribute to an approximation and harmonization of clinical trials at the European level. 

As a footnote, it is worth reporting that Revuelta says he received a good level of cooperation from ethics committees in conducting his research. He also says some complimentary things about 

, which has been reporting on the evolution of clinical trials regulation in Europe for many years, and in this column since the early 1990s, but that unfortunately there was no contact with or participation from the European Commission. I tried to get in touch several times, he said, but there was no interest.            

View from Brussels

A newly completed study of European ethics committees finds that the bureaucracy of each country determines the way the ethics committees operate.

European Ethics Committees?Still Salad Rather than Soup


The article Clinical Trials in India, by Radhika Bobba and Yamin Khan (

, February 2003, 5256) highlighted the tremendous clinical development opportunities in India. The authors rightly attribute Indias attractiveness as a clinical trial location to her large population, with diseases of both the developing and industrialized worlds, and a well-trained medical workforce.

In spite of the opportunities for rapid recruitment of treatment-nave subjects and the potential for substantial cost savings, however, U.S. and European pharmaceutical and biotechnology companies are reluctant to use India for their clinical development requirements. The reason for this reluctance is concerns about data quality, study ethics, bureaucratic regulations, and intellectual property rights (IPR) protection. Unless these concerns are addressed, notwithstanding the numerous newly opened contract research organization offices in India, persuading the global industry to deploy India as a major contributor to their multicentric clinical trials will be difficult.

I disagree with the authors statement that concerns regarding data quality from far-flung studies has dissipated. On the contrary, concerns about data quality and acceptability by FDA and EMEA are paramount for drug developers considering a nontraditional country for clinical trials. These concerns can be allayed by selecting well-trained investigators that are conversant with International Conference on Harmonisation (ICH) good clinical practice (GCP) guidelinesalso by ensuring that the clinical research associates and study monitors are trained in GCP and supported by standard operating procedures that are compliant with GCP and GLP (good laboratory practices). Additional quality assurance may be provided by international resources with experience of auditing other nontraditional clinical trial locations, for example, Central and Eastern Europe. Preliminary experience suggests that the clinical data from India is of world-class quality, but we must make every effort to maintain this standard.

As the article points out, some debate about the ethics of performing clinical trials in developing countries exists. The almost overzealous regulations prescribed by Schedule Y of the Indian Drugs and Cosmetics Act (Schedule Y, Requirement and Guidelines on Clinical Trials for Import and Manufacture of New Drug, The Drugs and Cosmetics Rules, India, 1945) are intended to safeguard Indian subjects. More recently, the Drugs Controller General of India adopted ICH GCP guidelines, including those related to informed consent and the absence of subject payments. Inclusion of India in global clinical trial programs is not third world exploitation. It enables one-sixth of the worlds population to access the benefits of biomedical innovation.

The article comprehensively describes Indias bureaucratic clinical trials regulatory processes. An in-depth and up-to-date knowledge of the regulations, along with experience of interacting with the regulatory authorities is essential for international companies seeking to conduct their clinical trials in India. 

Lastly, the global ethical pharmaceutical industry has reservations about conducting their pivotal clinical studies in India, because of Indias historic exemption from the World Trade Organization IPR regulations. India has committed to adhere to international IPR standards, however, and it will enforce all product patents registered after 1 January 1995. Indias determination to emerge as a leader in the global software industry is driving much of the recent progress in IPR protection by the Indian legal system. Hence, concerns about inadequate IPR protection for drugs undergoing clinical development in India are a hangover from a previous era. More so as physical access to the drugs has never been a requirement for successful reverse engineering by Indias generic pharmaceutical industry.

I endorse Bobba and Khans observation that India is viewed as an important global resource for clinical trials and data management services. Unless the tacit concerns of the global pharmaceutical industry are effectively addressed, however, the opportunities in India will remain underused.

Managing Director, PerinClinical Ltd, UK.
email: nermeen.varawalla@ periclinical.c o.uk
www.periclinical.co.uk

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