Last year may well be remembered as a public relations nightmare for the clinical trials industry. 

Early in 2004, the American Medical Association and the publishers of prestigious, peer-reviewed medical journals such as the 

 called for a government-based clinical trial registry to provide greater disclosure of drug risks in order to address potential bias in industry-sponsored clinical trials. That same month, the New York attorney general filed a lawsuit against GlaxoSmithKline for deliberately suppressing negative clinical trial results for its antidepressant drug Paxil. Dr. Angell's controversial and highly publicized summer 2004 book, 

The Truth About Drug Companies: How They Deceive Us and What to Do About It

, argued that conflicts of interest guide industry-sponsored trials.  

Later in the year, Merck withdrew its blockbuster COX-2 inhibitor Vioxx due to the drug's elevated risk of heart attacks shown in a large clinical trial. The Office of the Inspector General next released a survey showing that one-third of FDA scientists have doubts about the agency's ability to monitor the safety of new therapies during the review and approval process. And late in 2004, clinical research results showed elevated risk of heart attack and stroke with Pfizer's widely used COX-2 inhibitors Celebrex and Bextra. The press also reported on one study suggesting increased risk of cardiovascular events with over-the-counter drug Aleve. 

Poor public relations in 2004 are arguably part of a longer, five-year downward spiral that the clinical trials industry has endured and largely ignored. Indeed, some of the media's scrutiny and skepticism has been warranted. In 1999 and 2000, several tragic deaths of study volunteers participating in government- and industry-funded clinical trials (e.g., Gage Stevens, Jesse Gelsinger, Ellen Roche) were widely publicized. In 2001, the Office of the Inspector General released a report documenting a stretched and failing human subject protection system. That same year, the Food and Drug Administration reported dramatic increases in the number of complaints filed against investigators for noncompliance and fraud. In 2002, the Institute of Medicine issued its report calling for major reforms to the informed consent process.  

An assessment of major newspaper coverage during the past five years shows that the frequency of articles on the clinical research enterprise is increasing, but the number of negative articles is growing at a disproportionately faster rate.

 published its now-famous cover story "How Medical Testing has Turned Millions of Us into Human Guinea Pigs." The media's reference in this article—and in dozens more since then—to study volunteers as "Guinea Pigs" fails to acknowledge the profound decision that millions of people make each year when they give their consent to participate. The article also neglects to report that volunteers are active participants in a study and that they have the option to withdraw at any time. Sadly, clinical research professionals in government, foundations, and industry have done remarkably little to address the media's incomplete, sensationalistic, and ill-informed portrayal. Yet the public and prospective volunteers derive most of their exposure to—and education about—the clinical research process from the media. 

Public and volunteer communities know nearly nothing about clinical research and the important role that each party plays in the process. Historically, the clinical research community has relied heavily on the informed consent (IC) process as the primary means of educating study volunteers. Not only is the IC process reaching a narrow subset of the communities that it must educate, but also recent assessments of the process show that it is failing to live up to its intended purpose. According to a 2002 report, for example, the Institute of Medicine found the focus of the IC process to be largely the review of lengthy and confusing documents designed to protect the investigative site from liability. 										

Although the informed consent process invites study volunteers to ask questions freely, more than 70% of volunteers say that they do not even know what questions to begin to ask. Following informed consent form review, more than 85% of volunteers claim to understand the duration of the study and that they can withdraw at any time. But one-third of volunteers report that they did not understand that their clinical trial may carry additional risk and discomforts compared to a standard treatment.

 Only 17% of volunteers report that they sought input from other trusted sources. And 14% of volunteers say that they did not even bother to read the informed consent document prior to signing it.

The public and prospective volunteer communities also derive some education about the clinical research process through seeing study advertisements and promotions. According to a 2004 poll of nearly 6,000 adults, more than two-thirds (69%) were exposed to information on clinical research studies through television, radio, print media, and via Internet advertising. One out of seven adult Americans are exposed to information about clinical research studies from their primary or specialty care physician.

 Without broad understanding and context, however, recruitment advertising and promotional messages are met with at best passing curiosity from the public and prospective volunteers. According to recent public opinion polls, 94% of Americans perceive that clinical research is important to advance medical knowledge, but less than 20% of those diagnosed with severe and life-threatening illnesses report considering clinical trials as a health care option.

 Despite a wealth of online information available today, less than 5% of the general public knows where to find information about relevant clinical trials.

The medical and health professional communities are largely absent from educating the public and prospective volunteer communities. Of the 700,000 board-certified physicians in active community practices, less than half report referring their patients into clinical trials with an average referral rate for each physician of less than one patient per year.

 In 2004, less than 10% of the total number of volunteers completing clinical trials came directly from physician referrals. This is primarily due to health providers lacking adequate information and context with which to make informed decisions on behalf of their patients.

Growing coverage of the clinical research enterprise in the media is highly problematic. Whereas research sponsors and investigators tend to communicate with journalists when they are ready to announce a medical breakthrough, the media tends to focus on human mistakes, concealment, fraud, and corruption. As a result, there is a long-standing disconnection between the media and clinical research professionals. 

Most journalists have little to no formal knowledge about clinical research and they have virtually no time to learn as they rush to meet tight editorial deadlines. Facing a crunch, and due in part to patient privacy and confidentiality, many journalists must resort to interviewing the same study volunteers featured in past articles—typically the ones who are most vocal and often the whistle-blowers. Reporters are often looking for a hook—a storyline that will catch the reader's attention, possibly even garner a journalistic award. Many have been trained to dig for the negative stories and exposés.  

Research sponsors rarely, if ever, respond to media coverage as government and corporate employees are usually instructed not to interact with the media for fear of bringing more attention to a story, or of appearing defensive and self-serving. As a result, the public is largely receiving a one-sided view of the clinical trials industry in the media. 

Popular culture is also unbalanced. In those rare instances when clinical research is depicted in novels and in film, it is typically portrayed as clandestine and corrupt.

 These portrayals provide the necessary vehicles to create thrilling and intense fiction. In John Le Carre's book 

, for example, a health care activist is murdered before she is able to expose a large pharmaceutical company that has been exploiting vulnerable African study subjects. And in the film 

, Harrison Ford plays a physician wrongly accused of the murder of his wife. Ford is able to exonerate himself when he proves that the murder was part of a cover-up by a colleague who has been falsifying clinical research data to support a drug for a company in which he is a major shareholder. 

Without public education, support, and involvement, research sponsors and investigative sites are spending ever higher levels of resources on patient recruitment and retention with marginal—if not diminishing—results. During the past decade, spending on patient recruitment programs by investigative sites and research sponsors has grown by 16% annually, reaching more than $500 million in 2003.

 In that same period, volunteer randomization rates have declined steadily. According to reports from several hundred investigative sites and analyses of study completion records, nearly 45% of volunteers were enrolled in clinical trials in 1984. In 2003, randomization rates declined to less than 25%.

 And whereas one out of every six enrollees dropped out of clinical trials in 1984, an average of 27% dropped out of clinical trials in 2003

 Figure 1. The recruitment and retention challenge.			

Presently, investigative sites report that more than 90% of all clinical trials must extend their original study timelines in order to enroll the requisite number of volunteers.

 Sites attribute these enrollment delays to both the unrealistic timelines set by research sponsors and to the high level of difficulty in recruiting and retaining study volunteers. 

Government and industry-funded research sponsors now expect significant project delays as they seek approximately 2.6 million study volunteers to complete their studies each year.

 It is estimated that only 4%-6% of eligible patients who suffer from severe and life-threatening illnesses take part in U.S. clinical trials today.

Clinical research sponsors have turned their attention to recruiting volunteers from markets abroad—typically from ascending regions that include Latin America, Central and Eastern Europe, India, and China. These regions offer well-trained professionals, large numbers of treatment-naÃ¯ve and motivated patients, and lower relative costs. During the past five years, clinical research spending in ascending regions has grown by 45%-60% annually.

 But sponsors have done a poor job of explaining these strategies and practices to the media and the public. As a result, the media tends to portray the conduct of clinical trials overseas as exploitive and financially motivated. 

Regulatory agencies and the clinical research community have responded to public confusion and concern by implementing reforms designed to assure higher levels of compliance and reduce errors that might result in physical and ethical harm to study volunteers. Since 2001, a growing number of universities have established clinical research degree programs. The Department of Health and Human Services has implemented new privacy and conflict-of-interest disclosure  guide lines. Two agencies—The Association for the Accreditation of Human Research Protection Programs and the Partnership for Human Research Protection—were established to accredit institutional review boards. In addtion, trade groups including the Drug Information Association and the Association of Clinical Research Professionals have developed investigator certification programs. 

This past year, prompted by GSK's alleged failure to disclose clinical research information about Paxil and Merck's withdrawal of Vioxx, public and policy-maker outcry for greater transparency and comprehensive disclosure of active clinical trials and study results came to a head. Industry sponsors, including Eli Lilly, GlaxoSmithKline, and Pfizer, announced programs to provide comprehensive listings of clinical trials online. The industry lobbying group PhRMA (Pharmaceutical Research and Manufactures of America) also launched a clinical trial results Web site. 

These reforms and measures are an important step, but they are not nearly enough. They begin to address the need for greater transparency and disclosure, and they satisfy regulatory agency and research sponsor requirements to minimize potential errors, noncompliance, and fraud. However, they fail to acknowledge and address the fundamental need to educate and engage the public and prospective study volunteers. As such, these reforms will only be marginally effective until these communities understand why they are necessary and how they will influence and inform decision-making about the risks and benefits of clinical research participation and new medical therapies. 

Recent polls conducted among more than 5,800 American adults suggest that public trust in the clinical research enterprise is waning, with the highest levels of distrust existing among minority communities.

 (see Figure 2). The clinical trials industry must act now if it is to better inform and engage the public and prospective volunteers as partners in this process. 

Figure 2. Ethnic differences in perceptions of clinical trial safety.			

Long overlooked, the clinical research enterprise must proactively raise the overall level of public awareness, must properly and fully inform the public and prospective volunteers, and must establish and build a stronger connection with the many vital stakeholders on the periphery. Broad outreach and advocacy are critical practices that must be utilized to raise public awareness and understanding of the clinical research process and the benefits it brings society. 

Outreach and advocacy programs are already being used by a small but growing number of investigative sites and contracted clinical service providers to support patient recruitment efforts. Examples of typical "grass roots" initiatives include clinical research professionals attending health fairs; providing free health screenings at community centers; listing trials in health association and health support group newsletters; and speaking at community events. 

Reports on the results of these efforts show that advocacy and outreach has the potential to dramatically impact prospective volunteer interest in study participation. Community outreach efforts have been shown to more than double the rate of prospective volunteer inquiries in a closed head injury study; nearly quadruple the inquiry rate in a recent study of ulcerative colitis; and increase physician referral rates by 71% on a study of a new medical therapy for type II diabetes.

Current outreach and advocacy programs are promising but limited. They are project specific and therefore not designed to provide a general education. They are short-term in their focus as they are intended to fill individual clinical trials. Once enrollment targets have been reached, these programs are terminated. Their design and implementation also vary from project to project. As such, they fail to provide a consistent and coordinated message. 

To be effective and successful, broad education, outreach, and advocacy programs must have the support of the entire clinical research professional community. These programs must be well-coordinated and integrated into all clinical research activities. They should have a consistent message and should focus on raising awareness and engaging stakeholders on the periphery of the enterprise, including the medical community, government officials, family and friends of potential volunteers, and the media. 

Specifically, a comprehensive, focused set of initiatives is needed to introduce the public, prospective volunteers, health professionals, the media, and policymakers to the large amount of clinical research activity being supported and conducted within the community each year. These initiatives should include: 

1) Educational material to assist volunteers in framing the questions to ask of the research community in order to protect their safety and rights, and to inform the profound decision to participate in a clinical trial. These materials should also address the unique educational needs of special populations (e.g., pediatric and geriatric populations; communities of color and gender-based populations). 

2) Broad-based outreach and advocacy programs to convey the important role that health care providers play as partners in the clinical research process. These programs should also assist the media and policymakers in understanding the processes and requirements of developing new medical interventions and participating in clinical research. 

3) Messages and images that put a face on the many professionals who dedicate themselves to managing and conducting clinical research and elucidate why R&D is a lengthy, costly, and labor-intensive process that holds the potential to significantly benefit and improve public health. 

4) Most importantly, an open acknowledgement of society's  appreciation for the many people who give the gift of participation each year. 

The National Institutes of Health and the Food and Drug Administration are increasingly recognizing the critical and timely need for broad education, advocacy, and outreach. This past year, the NIH announced the creation of a Public Trust Initiative to instill higher levels of public confidence in government-funded clinical research.

 The FDA recently announced its interest in raising overall awareness of the importance of clinical research to public health and the role that the agency plays in that process.

 In an effort to increase the transparency of industry-funded clinical trial results, PhRMA also recently launched a new Web site

 that includes educational information for the public. 

In March of 2004, the Center for Information and Study on Clinical Research Participation (CISCRP) was established to educate and inform stakeholders including the public, prospective volunteers, health providers, policymakers, and the media. Based in Boston, CISCRP is an independent, nonprofit organization that derives its funding from a diverse base of supporters that includes government agencies, foundations, corporations, and individual clinical research professionals. As a result, CISCRP is well-positioned to provide broad education, advocacy, and outreach across all areas of government- , foundation- , and industry-funded clinical research activity.  

Since its inception, CISCRP has produced and released the nation's first public service announcements for radio, television, and print to raise awareness and national pride in the clinical research enterprise, and to express appreciation for the millions of people who volunteer to participate in clinical trials each year. CISCRP has compiled contact lists of professionals and experienced study volunteers who have given their consent to speak at community events, lecture medical schools, and be interviewed by the media. It has hosted and participated in numerous advocacy, professional, and community events where broad-based educational materials have been distributed. CISCRP has organized and implemented a Clinical Research Public Perception Summit that brought together members of the clinical research community and the media. The organization was selected to collaborate with the FDA and the NIH on general outreach and advocacy projects. And CISCRP developed and launched a resource-rich Web site at 

. These are but a few examples of CISCRP's many programs and initiatives.

It is time for clinical research professionals to acknowledge that the public and volunteer communities have a severely limited and incomplete understanding of the clinical research process, and the important role that each party plays in that process. These stakeholders, and others on the periphery of the clinical research enterprise—including health care providers, the media, and policymakers—are not engaged in the process. Broad education, outreach, and advocacy are needed at both the national and local levels if we are to partner with these vital stakeholders in order to safely realize the profound benefits of biomedical research to society. 

An Industry in Evolution: Sourcebook of Charts and Statistics Providing Analysis and Insight into the Clinical Trials Industry

2. K. Getz, "The Informed Consent Process," 

3. K. Getz, "The Informed Consent Process," 

4. HarrisInteractive, "Views and Attitudes of Clinical Research Studies," 

Articles

Feature Article

During the past decade, spending on patient recruitment programs has grown 16% annually. In that same period, volunteer randomization rates have declined.

Educating the Public: A Critical, Unmet Need

According to a recent 2003 Impact Report by Tufts Center for the Study of Drug Development, pharmaceutical companies now have an average total R&D cost of $802 million per new drug entity and $897 million, if both pre-and postapproval phases are included.

 Pharmaceutical companies must initiate their clinical trials in an increasingly efficient manner to ensure thorough protocol development, prompt regulatory readiness, high quality, cost-effective study initiation training, accurate and efficient study supply delivery, steady enrollment, quality data collection, monitoring, reporting, timely issue resolution, datalocks, and study closeout. All of these functions must be done within a set budget and timeline. 

This is a difficult, multitask assignment that might become even more difficult as the medical industry braces for the aging baby boomers. Couple this with potential investigator shortfalls, stricter regulations, and tighter trial budgets as the industry tries to control drug development costs. What might be a potential option for accomplishing the challenge of developing drugs while lowering costs and decreasing development times? 

Clinical investigative site networks, defined as a group of independent clinical sites based upon specific qualification criteria that function as one entity, may be a new option for offsetting the increase in R&D costs. The networks may differ within and between therapeutic areas. In addition, they may offer a variety of services and have some similarities to site management organizations (SMOs) and contract research organizations (CROs). 

 Table 1. Regulatory readiness (protocol receipt to study drug shipment-in working days)						

The entire network is managed by a central administrative staff, as per set network procedures. The central administrative team often oversees and streamlines financial, regulatory, safety, data management, business processes, quality assurance, and site selection concerns for each trial. Like an SMO and possibly a CRO, the central administrative staff would determine the appropriate number of sites and locations for participation in each trial based on the trial criteria, network needs, and the current trial portfolio within the network. Unlike most SMOs and CROs, however, the clinical investigative network functions as a participating clinical site by performing required trial functions that include financial functions, regulatory readiness, data management, and safety reporting. 

In contrast to most CROs, which are often contracted to perform specific sponsor functions, networks require sponsor monitoring. Networks are regionally structured and further divided by disease state. Each region is assigned a lead investigator for the specific disease state based on the investigator's expertise. The investigator serves as a representative on a central disease state committee and as the lead facilitator/communicator for all trials involving that particular disease state being conducted in their region. In addition to the regional lead investigator for each disease state committee, an advisor (primary or principal investigator) functions from within the central network office and facilitates/coordinates the disease state committee. The advisor is responsible for advising, leading, and coordinating the regional lead investigators. 

The central administrative staff coordinates all public relations for the entire network. As potential trials are offered to the network, the central administrative staff works with the primary investigator or advisor to initiate a scientific review of the potential study protocol, involving the appropriate disease-specific committee and thus each of the regional lead investigators. If the protocol is approved, then the legal/financial component of the central administration staff initiates contract and budget negotiations with the trial sponsor. 

Table 2. Enrollment rates (Network A vs. all other single sites participating in same trial; U.S. only trials)			

The regulatory readiness process, including informed consent document (ICD) development and the institutional/ethical review board (IRB) review process, are initiated within the regulatory component of the central administration staff. Networks typically utilize a central IRB for the entire network consisting of proper membership as per 21 CFR 56. Supply shipments such as lab kits, study drug, and case report forms are coordinated by the central administrative staff working with the trial sponsor. Study initiation training is coordinated for all network participants by the central administrative staff. Upon receiving IRB approval, completion of the regulatory readiness process and the study initiation training, the study drug is shipped by the trial sponsor to the network so that enrollment may commence. 

Clinical investigative site network benefits

One significant benefit is that the sponsor works through a central administrative staff rather than several clinical administrative offices, reducing the number of contacts and streamlining study communication. Specific clinical processes are coordinated through one central office, reducing the timeline associated with completing these tasks. For example, the contract, IRB approvals, ICD, and privacy content negotiations are streamlined as all reviews are handled by one central legal group, financial group, and IRB, as compared to dealing with multiple clinical sites and committees. Scientific review of the study protocol is also streamlined, since one scientific committee handles reviews with one review process for the specific disease state. A high level of efficiency and quality may be reached due to the consistency associated with a central staff and set processes. Efficiency and quality lead to faster trial initiations and completion, as indicated in Tables 1-3, which were compiled based upon three trials conducted using both the network and single-site models. 

Table 3. CRF query rates (Network A vs. all other single sites participating in same trial; U.S. only)						

Issue resolution can be streamlined due to the network model. The network quality assurance department helps to ensure compliance and prevention of issue trends by maintenance of network processes, procedures, training, and periodic audits of the satellite sites. Clinical networks often utilize a central study drug/lab kit ordering and delivery system to maximize efficiency. The clinical trial management systems are usually electronically based and are located on the network's secure intranet. The centralized pharmacy process allows for the sponsor to ship initial study drug to only one location, which can minimize overhead for both the sites and sponsor. 

Although a clinical investigative network may be more expensive in comparison to a single-site model, this may be due to clinical networks having larger study initiation and per-patient fees to cover the central administrative costs. However, benefits may outweigh the costs if the sponsor considers the number of actual sites that are being initiated for the larger fees, the quality and timeline impact due to better process and staff consistency, and the potential enrollment impact on the study. The clinical investigative network also provides increased exposure for trials that are conducted within the network. This is often accomplished by utilizing network intranet systems, collaborations, and enhanced communication processes through network newsletters and monthly update teleconferences. Another potential benefit of the clinical network is that smaller clinical institutions may have an increased opportunity to participate. The patients and physicians can benefit since more trial options are available. 

Figure 1. A section of an example clinical investigative site network trial initiation checklist.			

This network model may not always be the most efficient design for every clinical trial, due to the increased time that it takes to establish initial network processes and procedures. Most likely, these trial types will be small, early-phase trials or trials with shorter enrollment periods. The sponsor must consider all of the network benefits and issues as summarized in Table 4.   

Conducting an initial strategy meeting in the early planning phase may be helpful in understanding the clinical network structure, clinical processes, and how the network differs from the typical single-site model. Using discussion tools, as illustrated in Figure 1, may be beneficial to ensure the right questions are asked at the right time and that detailed minutes are recorded. Key topics for discussion might include regulatory readiness and timelines, including FDA 1572 process, ICD review/approval, IRB structure to ensure 21 CFR 56 compliance, safety reporting, drug accountability, and monitoring (centralized versus decentralized). The use of eClinical processes and tools such as virtual training processes for study start-up training, document repositories for secure document exchange, and electronic data capture might be another important topic. This discussion could help to ensure compliance with 21 CFR 11 and that the end user computers are properly prepared for upcoming tool use. In a recent 

 article, Carpenter stated, "Initial 21 CFR 11 compliance assessments of a site's systems should begin during the site selection process."

 Conducting key topic discussions early in the planning phase may help to ensure that well-defined clinical processes are established with the investigative network. 

Table 4.  Clinical investigative site networks						

The sponsor should consider the probability and the benefit of conducting additional future trials within the network, and thus the benefits of developing an alliance between the clinical investigative network and the sponsor. The formation of an alliance agreement will facilitate a commitment from both sides, and lead to a true partnership so that both parties feel true ownership and will work together to develop the most efficient and compliant clinical processes. The alliance agreement should list specific high-level objectives like compliance, ethics, quality, commitment, process development, level of participation, communication, and "high level" timelines and metrics. Experience has shown the resources spent in the early stage of the alliance formation and on procedure and process development have paid off throughout the life of the alliance, with increased process comprehension and compliance, reduced process issues with each trial, improved quality, faster trial initiations, and shorter trial timelines, while also reducing overall costs. 			

1. Tufts Center for the Study of Drug Development, "Impact Report: Post-Approval R&D Raises Total Drug Development Costs to $897 Million," 5 (3) May/June 2003. 			

2. J. Carpenter, "21 CFR 11 Compliance at Investigator Sites," 

* RPh, is a senior medical consultant with the U.S. Medical Affiliate, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, (317) 276-8405, email: 

 MS, is a clinical plans manager with the U.S. Medical Affiliate, Eli Lilly and Company. 

 BSN, RN, OCN, is a clinical operations team leader with the U.S. Medical Affiliate, Eli Lilly and Company.

* To whom correspondence should be addressed.

The benefits of clinical site networks may outweigh the costs when sponsors consider the enhanced quality and timeliness as well as potential impact on enrollment.

The Clinical Investigative Site Network

Recent scientific breakthroughs promise significant payoffs for human health, with new discoveries opening the door to new pharmaceutical and therapeutic agents. But the potential health benefits of these discoveries are often threatened during clinical development by high risk of failure, high development costs, and a decline in the number of successful products reaching the marketplace. Since 1993, the U.S. Food and Drug Administration (FDA) estimates that yearly U.S. pharmaceutical R&D spending has more than doubled, while the number of new drug and biological submissions has decreased dramatically (see Figure 1).

While a variety of factors can contribute to this decline, failure to reach the marketplace can in part be caused by not meeting stringent regulatory requirements, including good clinical practices (GCP) and the Code of Federal Regulations (CFR). Also adding to the failure rate are safety problems and effectiveness. Given these circumstances, the FDA estimates that a drug entering Phase I testing has only an 8 percent chance of reaching the marketplace.

 Figure 1. Number of submissions of new molecular entities (NMEs) -drugs with a novel chemical structure-and biologics license application (BLA) submissions to FDA over a 10-year period. Similar trends have been observed at regulatory agencies worldwide.			

Having well-trained study coordinators can be a key success factor for pharmaceutical and biotechnology companies facing these issues. As the individual responsible for day-to-day clinical trial activities, it is the study coordinator who can ensure standards are met and that any problems are spotted and taken care of immediately. Yet many of these professionals often go without the training needed to ensure the best results. This article discusses the importance of specialized training for study coordinators and identifies the curriculum that can offer value where theoretical training falls short. 

Study coordinators come from a variety of medical backgrounds, from medical assistants to nurse practitioners. Although familiar with the standard tasks associated with the coordinator role, they may not be as well-versed on the particulars associated with clinical trials in specific therapeutic areas, including the gathering and reporting of quality data. Training can help, but it often falls short of meeting specific needs. Results of a survey sent in coordination with the Spanish Lung Cancer Group and published in March 2004 by BMC (BioMed Central) Medical Research Methodology found that less than half of the oncology study coordinator respondents had received specific training in oncology, clinical research, or GCP. Many of these same study coordinators were found to be involved in all aspects of clinical site coordination, as well as preparing IRB submissions, scheduling patient CT appointments, and assessing inclusion/exclusion criteria—tasks that require specialized training beyond what many have actually received.

This lack of training can present a barrier to meeting regulated research expectations—the EU Directive, Health Insurance Portability and Accountability Act (HIPAA), and other regulatory and legal concerns. It increases the risk that standards may not be met because the study coordinator may not be aware of them. It also shifts the responsibility of preparing and managing study coordinators from the investigators to the individual study sponsor or monitor. This most often occurs during the course of clinical trials, which can interfere with a trial's process and timeline. 			

Usually academic in nature, traditional training courses teach the theoretical and historical aspects of clinical research and provide an abstract framework for conducting clinical trials. Other typical "how-to" programs focus on protocol-specific tasks such as how to administer informed consent. But this training does not successfully address issues that may be related to all the tasks associated with a study coordinator's role.  							

Between these two levels of education, there exists the practical stratum of knowledge that many study coordinators are lacking. Theoretical and tactical aspects should be bridged with the "how" and "why" of the study coordinator's role as it relates to a particular therapeutic area, product class, or country. This requires a curriculum that balances an explanation of the study coordinator's role, addresses specific aspects of job performance, and highlights the anticipated issues associated with a clinical trial. 

For example, multiple breast cancer trials are performed throughout the United States, making competition for patient participation a major challenge. Study coordinators should learn when to anticipate slow recruitment rates and alert the organization conducting the trial, so that certain recruitment strategies can be changed if needed. 

The need for this level of training grows with the complexity of clinical trials. Current clinical trials in oncology, for example, require the collection of multiple and often complex endpoints and sometimes use new, sophisticated technologies and tools for disease diagnosis and drug response measures. These factors have specific technical demands and need to be performed on a strict schedule as specified in each study's protocol. A well-developed knowledge base for study coordinators can ensure that these requirements are met sufficiently. 

New training programs are emerging that offer a comprehensive approach to preparing study coordinators. They are designed to go beyond empirical training, providing a more complete set of tools for success. The following are specific topics to look for in a more complete study coordinator training program. 

 Figure 2. Study coordinators are responsible for communicating with many professionals during a trial.

Communicating effectively with all stakeholders.

 "Communicating in the Information Age," an April 2002 article in 

, identified that a project team performing poorly will often cite a breakdown of communication as the main cause of the problem.

 Study coordinators play a key role in preventing this problem. In addition to coordinating health care teams and caring for patients, study coordinators are responsible for communicating with trial personnel at varying levels of involvement, from sponsors to primary physicians (see Figure 2). Without adequate training, managing the shifting communication styles among these groups can be stressful. Training should arm study coordinators with adequate communication skills and the tools that allow them to disseminate information using the best methods, approaches, and technologies for each situation. 

Understanding regulatory requirements and issues.

 Study coordinators need to understand the regulatory responsibilities of each organization involved in a clinical trial. Understanding these requirements and issues results in improved trial compliance. Look for a training course that identifies the regulatory responsibilities of site staff, ethics committees, and institutional review boards (IRBs), as well as the regulatory aspects of clinical trial documentation, legalities of informed consent, and resources in the event of a regulatory audit or citation. Ethics is also an important consideration. Training should help study coordinators consider three key ethical questions when recruiting for any clinical trial: 

1) What are some of the things you need to think about to ensure the subjects are making a decision based on what they think is best for them? 

2) How can you be sure that the subjects have truly given their consent or have truly volunteered?  

3) What are the conflicts that could interfere with or influence an individual's willingness to volunteer or participate? 

  Informed consent, which is a main element in protecting the rights and welfare of study subjects, is not simply a matter of having a subject sign a piece of paper. When creating informed consent, investigators are required to know and adhere to specific regulatory requirements related to a trial's therapeutic area. An informed consent form, for example, should be submitted for written approval by an IRB or international ethic committee (IEC) prior to the beginning of a trial and whenever important new information is added or changed.

 This responsibility, although typically that of an investigator, is often delegated to study coordinators who may not have previous knowledge or experience in the area. A consent form can fail its objective if a study coordinator does not understand the importance of word choice, regulatory requirements, or the overall trial objective. 

 On average, the FDA conducts Bioresearch Monitoring (BIMO) Program audits on more than 700 clinical investigator sites, 250 IRBs, and 100 CROs each year.

 Several of these inspections have yielded evidence of problems. In 1993, for example, the FDA penalized a large California university IRB for infractions that included failure to report deaths.

 Understanding the importance of FDA audits and IRB practices, and using proper documentation, can help clinical trial investigators and sites avoid audits and subsequent penalties. Study coordinators often learn how to prepare for an audit and how to recognize what the auditor is looking for. But another, often-overlooked aspect is for study coordinators to know how to conduct themselves during an audit. This includes giving auditors access to every piece of information and ensuring complete transparency. 

 One of the major factors affecting a trial's timeline is the implementation of a contract with an investigator site. It often takes several months to receive approval by representatives for both the investigator and sponsor. Study coordinators can help improve the process by ensuring that it is reviewed and approved by the participating physicians or hospitals in a timely manner. 

Developing a budget that accurately reflects the cost of performing a clinical trial is also a very complex process. Factors affecting the cost can include treatment regimen, therapeutic area, study phase, required clinical assessments, number of visits, and whether the investigator contracts independently or is affiliated with a teaching institution or hospital. These factors are continually changing, and so are the best practices used to deal with them. Study coordinator training courses should present solutions including creating a payment system, maintaining a tracking system to address budgetary issues, and offering skills in budget negotiation. 

 Study coordinators should be familiar with various study designs, the advantages and disadvantages of each design, the process of randomization, and the reason for inclusion/exclusion criteria. For instance, a study designed for a hypertension trial will not be successful for an oncology trial. Likewise, an oncology trial that is testing a biological compound may not have the same primary endpoint in its trial design as one testing a cytotoxic agent. Understanding the differences helps in prioritizing issues during the day-to-day implementation of research protocols. Mastering the overall study design and randomization schema can also substantially improve study compliance, resulting in the reduction of inadvertent protocol deviations and decrease in the subject attrition rate in clinical studies. 

The incorporation of continued training is an important element that many popular programs neglect to focus on. Leaders in training now recommend that topics ranging in subject level from beginning to intermediate—including those stated previously—be covered over the first several years of a study coordinator's career. Training may begin with a "basics" course with background sessions in ethics, contracts and approvals, and informed consent. It should then move into intermediate training to provide practical, more therapeutic-specific, mid-level training. Look for a program that provides additional value, such as those that offer accreditation credits for SoCRA or other professional certifications. Other offerings to look for are "handbook" courses addressing such details as required approvals, and even email networks and other tools to provide study coordinators with access to peers. 			

This mid-level approach is increasingly being used in various regions and has been a part of the Canadian clinical research industry for several years. The Northern Alberta Clinical Trials and Research Centre (set up as a joint venture of the University of Alberta and Edmonton's Capital Health Authority) provides orientation, education, and networking to more than 200 study coordinators in Northern Alberta. Its program represents a progression of training during the first two years of a study coordinator's career. This format offers two distinct benefits. It allows for repeated exposure of important topics for better comprehension and retainment, and presents key information at the most pertinent time during a study coordinator's professional development. 

Although the value of study coordinator training in clinical research is generally well accepted, a quantitative framework to assess the outcomes has not been formally established to date. More qualitative benefits can be observed that help make the connection between effectively training study coordinators and achieving clinical research success. These include improved site relationships, higher quality of work done at sites, and better facilitation of dialogue among all study participants.  

By better preparing study coordinators for their responsibilities, the quality of work and compliance with expectations and regulations can increase. The benefit of this applied knowledge is the ability to put best practices into place to substantially improve compliance. Training is the key to ensure that study coordinators are prepared not only theoretically but practically as well, being able to effectively adapt to different situations and different requirements. New trends in training are exceeding traditional limitations to provide this level of knowledge. Organizations taking advantage of these trends are helping to shape the increasing expectations of today's clinical trials.  

1. U.S. Department of Health and Human Services, 

Innovative or Stagnation: Challenges and Opportunity on the Critical Path to New Medical Products, 

www.fda.gov/oc/initiatives/criticalpath/whitepaper.html

2. F. Rico-Villademoros, T. Hernando, J.-L. Sanz, A. López-Alonso, O. Salamanca, C. Camps, R. Rosell, "The Role of the Clinical Research Coordinator-Data Manager-in Oncology Clinical Trials," 

, 4 (6) 1471-2288 (25 March 2004) http://

3. R.J. Anderson, "Communicating in the Information Age: It's Still All About Human Behavior," 

4. U.S. Department of Health and Human Services, 

Guidance for Industry—E6 Good Clinical Practice: Consolidated Guidance

5. C. Hommel, "FDA's Oversight of Clinical Trials Overview of GCP Bioresearch Monitoring Program," PowerPoint presentation, http://

www1.va.gov/resdev/fr/ao_compliance_training/FDAs_Oversight_of_Clinical_Trials.ppt

6. R.C. Thompson, "Protecting 'Human Guinea Pigs,'" 

FDA Consumer Special Report on New Drug Development in the United States

is training director with Endpoint Research and New Directions: Study Coordinator Training Program, 2595 Skymark Ave., Suite 210, Mississauga, Ontario L4W 4L5, (416) 282-8885, fax (416) 626-2063, email:   

Meeting today's drug development challenges by better preparing study coordinators

Training for the Real World

 have shown that random imbalance in clinical trials is a topic of lively controversy.

 During my interactions with trialists in industry, academia, and the public health sector, I have come across what I believe are serious misunderstandings regarding what randomization can and cannot do to underwrite the validity of statistical inferences from clinical trials. In this commentary I use games of chance to attempt a simple explanation of the issues.

I believe there are two misunderstood points regarding randomization. First, randomization in clinical trials enables one to deal validly with the effect of unmeasured covariates. In particular, in the absence of any prior information about the effect of treatment and of any knowledge about the actual distribution of covariates in the given trial under question, valid statements may be issued using simple analyses.  

 Table 1. Sample space for a game of chance involving two dice

Second, given knowledge of the baseline distribution, however, such simple statements are not valid and more complex analyses may be called for. 

These points will be illustrated using a simple example involving the rolling of two fair dice, a red and a black die. The dice are to be rolled red first, and a statistician is to make a bet regarding the outcome, which involves his correctly calling the odds so that the sum of the scores will be 10. The game is to be played in two different variants. In the first variant, although the dice are rolled in the sequence red then black, the score on neither die is revealed until the statistician has called the odds. The question is, "What odds should he call?" In the second variant, the result of rolling the red die is shown to the statistician before he has to call the odds.

The basic probability setup can be illustrated by Table 1, the "sample space" of all possible outcomes. The table represents the 36 possible combinations of scores from the two dice. The combinations where the total score is 10 are identified by parentheses. 

For the first game, the statistician can argue as follows. There are 36 possible combinations of results on the two dice, red = 1 and black = 1 , red = 2 and black= 1, and so forth on to red = 6 and black = 6. Each of these combinations is equally likely, but three of them yield a total of 10. Therefore the probability required is 3/26 = 1/12 and the odds are 1:11. 

Table 2. Probability of a total score of 10 given the red die score

For the second game the situation is as given in Table 2. If the statistician sees that the result of the first roll is a one, two or three, he can recognize that it is impossible that the total score will be 10. He therefore calls the odds as zero. On the other hand, if the result is four or higher, there is exactly one possible score on the second die that will produce a total of 10. Hence in each of these cases, the probability of a total of 10 is 1/6.  

In terms of Table 1, the statistician recognizes that the result must appear in a given row of the table and uses the possible results in that row only to calculate the probability. The statistician's jargon here is that the row constitutes a recognizable subset of the sample space.  

According to the great statistician, geneticist, and evolutionary biologist R.A. Fisher (who introduced randomization to the design of agricultural experiments), where such subsets can be recognized they, and not the sample space as a whole, must be used for inference. In fact in his book 

Statistical Methods and Scientific Inference,

 Fisher considered the case of a gambler throwing a die: 

Before the limiting ratio of the whole set can be accepted as applicable to a particular throw, a second condition must be satisfied, namely that before the die is cast no such subset can be recognized.  

Note also that the way that we obtained the answer for game two suggests an alternative way of reasoning for game one. The statistician can say to himself, "if I saw the red die, there would be half a chance that the probability of getting 10 would be zero and half a chance it would be 1/6. So, overall, my probability is a half chance of zero and a half chance of 1/6, so the odds are 1:11." 

Note that this approach yields exactly the same result for game one as our previous calculation. Averaging over all possible relevant subsets is equivalent to ignoring the existence of such subsets. This behavior is appropriate when the particular subset that applies cannot be recognized, 

. The result of the red die has not been revealed, therefore there is no recognizable subset and this behavior is therefore reasonable. 

Now consider a third game. A fair 12-sided or dodecahedral die is constructed. One of the 12 faces is marked with a cross. The statistician has to call the odds before the die is rolled. The probability of rolling the cross is clearly 1/12. 

Note that from the practical purpose of calling the odds, there is no difference between game three and game one. 

The result of the red die is analogous to the distribution at baseline once a clinical trial has been randomized. The total score of the two dice is analogous to the result observed at the end of the trial. Game one corresponds to a trial in which baseline variables are unobserved; game two corresponds to one in which they are observed. Game three corresponds to a trial in which as far as anyone knows, there simply are no prognostic covariates. Not only has the baseline distribution not been measured, it is unmeasurable because no one has any idea what it might be relevant to measure. 

The first misunderstanding is to treat games one and three differently. The odds that the statistician issues for game one are no less nor more valid than the odds issued for game three. It would be physically possible in principle for the results of the red die to be revealed, but the rules of the game forbid it. Hence, game two is formally equivalent to game three, and there is no point in worrying about what the value of the red die might be. The analogous error for a clinical trial is to query the validity of a correctly calculated treatment estimate and standard error for the case in which prognostic covariates might have been measured, but were not on the grounds that these covariates might be imbalanced. Physicians are particularly liable to commit this error. 

The second misunderstanding is to treat game two as if it were game one. Given that the result of the red die has been observed, it is simply incorrect to call the odds that apply to game one. The analogous mistake is to argue that in a   clinical trial in which prognostic covariates have been measured, the covariates can be ignored because one has randomized. This is an error to which (naÃ¯ve) frequentist statisticians are particularly liable. 

In my view, there are two implications of an understanding of what randomization can and cannot do in clinical trials. 

First, one should not use the fact that one has randomized as an excuse for ignoring baseline prognostic information in analyzing a clinical trial. Such prognostic information provides the means of distinguishing the particular clinical trial from the much larger set of trials one might have run in which the baseline prognostic distribution might have been different.  

For example, having observed a baseline difference of 3 mmHg in blood pressure between treatment groups and a difference of 8 mmHg at outcome, the relevant way to calculate the P-value is not to ask, "Given no treatment effect, with what probability would a randomized trial show a difference at outcome of more than 8 mmHg?" Rather, the question should be, "Given no treatment effect, with what probability would a randomized trial with a difference of 3 mmHg at baseline show a difference at outcome of more than 8 mmHg?" An answer to such a question can be provided by using the statistical technique called analysis of covariance. 

Also, given that one has taken account of relevant measured prognostic covariates and has randomized, there is no point worrying about the distribution of unmeasured covariates. In the absence of actual distribution in such covariates, the distribution they would have in probability over all randomizations is the appropriate distribution to use. This is analogous to the way that one may use the whole of the possible distribution of scores for the red die if one has not observed which score applies.  

A very similar issue arrives in insurance. An insurance company can appropriately set premiums for an individual using the statistics for a large set of similar individuals provided that it cannot be recognized that the individual differs in some way from the average in question. If the individual knows a relevant piece of information, such as the result of a medical or genetic test, then the average risk is no longer applicable. 

These simple points may seem so obvious as to be not worth stating. Yet in my opinion, they are often misunderstood. In fact, I was present at a regulatory hearing only a few years ago in which a regulator (not a statistician) argued that the results of a randomization in a double-blind trial were not valid because there was a run-in period after randomization. The regulator also argued that although those baseline values measured at randomization were comparable, the baseline values just prior to treatment might not be. There are several misunderstandings here. First, randomization does not guarantee balance. Second, balanced covariates may not be ignored. Third, the possible distribution of unmeasured covariates in a validly randomized trial does not invalidate the probability statements about the effect of treatment. 

Trialists continue to use their randomization as an excuse for ignoring prognostic information, and they continue to  worry about the effect of factors they have not measured. Neither practice is logical. 

1. M. Buyse and D. McEntegart, "Achieving Balance in Clinical Trials," 

2. S.J. Senn, "Unbalanced Claims for Balance," 

3. S. Day, J-M. Grouin, J.A. Lewis, "Achieving Balance in Clinical Trials," 

Statistical Methods, Experimental Design and Scientific Inference

, J.H. Bennet, ed. (Oxford University, Oxford, 1956). 

 PhD, is professor of statistics, Department of Statistics, University of Glasgow, Glasgow G12 8QQ, U.K., email:  

Guest Commentary

A simple game of chance clears up the confusion over what randomization can and cannot do.

Baseline Balance and Valid Statistical Analyses: Common Misunderstandings

Informed consent takes place in the brain. While that seems obvious, the implications of that statement go much deeper. To a great extent, both bioethics and federal policy are based on 17th century assumptions by philosophers such as Descartes—who knew nothing of the structure and function of the brain.   

The gut "feeling" that prospective subjects have about entering a clinical trial may not be so much a metaphor as a biological reality. Mark Hochhauser, PhD, IRB member, North Memorial Health Care			

Descartes' Error: Emotion, Reasoning and the Human Brain

, neurologist Antonio Damasio argues that reasoning is not merely an abstract philosophical concept, but primarily a biological function of the brain. Despite Descartes' widely accepted separation of mind and body—with its implications for the superiority of reason over emotion—Damasio uses data from brain-damaged patients to show how and why Descartes' mind-body separation is wrong.  

Emotion and reason exist in specific parts of the brain. The top cortical layer is involved with rational thinking and planning, while the deeper subcortical central area (the limbic system) is involved with emotions and their corresponding feelings. Philosophers may separate emotion from reason, but the brain does not.  			

Often implied in the emotional-rationality division is the assumption that emotion disrupts reasoning. But Damasio found that patients unable to experience emotion often exhibited irrational behavior—not more rational behavior. Recently, I was asked if I could suggest ways of removing emotion from the informed consent process. I replied that taking emotion out of the consent process could not be done. Even if emotion could be removed, its removal would not guarantee better (more rational) decisions by prospective subjects. In fact, without emotions, subjects would find it harder to make an "informed" decision since they would not have emotions or their associated feelings to guide them.  

, Damasio described emotions as public bodily behaviors that can be seen by other people, and feelings as private, more hidden reactions to those emotions. Based on the brain's evolution, he concluded that emotional reactions occur first, feeling those emotions second, and thinking about those emotions and feelings last. Emotions and reason are not separate, but integrated functions within the human brain. From this perspective, the consent process is first one of basic emotions—anger, fear, disgust, contempt, happiness, sadness, and surprise. Although psychologist Paul Ekman has found that such emotions can be seen in a prospective subject's facial expressions if one knows what to look for, subjects cannot always translate their emotions and feelings to into meaningful conversations with researchers.  			

Because prospective subjects might be afraid of a clinical trial, or disgusted by aspects of the consent process, or feel contempt (because of the Tuskegee Syphilis Experiment, for example), they will have emotions and the associated feelings that accompany them, but may be unable to put those emotions and feelings into words. While their decision to take part or refuse to take part in a clinical trial may actually be based on emotions, their rational explanation for their decision may make little reference to their emotions and feelings. Because we don't have a very good emotional vocabulary, what people feel and what people say isn't always the same.  

Plus, since the brain is connected to other parts of the body via the sympathetic and parasympathetic nervous systems, hormones and peptides, the "gut feeling" that prospective subjects have about clinical trials may not be so much a metaphor as a biological reality. The unique features of each clinical trial, when combined with individual biology and experiences, means that the consent process may be felt in the body as well as analyzed in the mind.

 PhD, IRB member, North Memorial Health Care.

A Closing Thought

Informed consent takes place in the brain. While that seems obvious, the implications of that statement go much deeper. To a great extent, both bioethics and federal policy are based on 17th century assumptions by philosophers such as Descartes-who knew nothing of the structure and function of the brain.

The Anatomy of Informed Consent

As the complexity of clinical development grows and the market for new medicines expands, it should come as little surprise that clinical trials have become truly global. The major drug development regions of the world are primarily North America, Europe, and Japan, but emerging markets such as those in Asia, Latin America, and Africa are playing a greater role in the global plans of pharmaceutical and biotech companies. This is illustrated by industry data showing that clinical trial spending in the Middle East and Africa rose from $10 billion (U.S. dollars) in 1998 to $75 billion in 2002.

Although clinical trials are now taking place in diverse regions across the world, companies face numerous new challenges when incorporating emerging regions into their clinical development plans. In North America, Europe, and Japan, the regulatory, ethical, and clinical research environments are fairly well defined, and so companies have sufficient previous experience to help them adapt to further changes in these regions. However, in emerging regions of the world, these environments are less clear-cut and guidelines acceptable elsewhere may not necessarily apply. 

Anyone wishing to work in so-called developing countries, such as those in Africa, must take great care that they do not come across as having a "superior attitude." Clinical trials carried out in developing countries must be run to the same high quality and ethical standards as elsewhere in the world. Everyone involved in clinical development has a duty to look after and care for patients involved in trials wherever they are. Commercial objectives should not compromise this stance. It is likely that difficulties will be encountered when running trials in regions such as Africa, but overcoming them can help provide valuable information for the development of a new medicine and can be a rewarding experience for those involved in such projects. 

Although this article will refer to Africa, it must be remembered that the region is vast and encompasses a range of countries (Table 1) with myriad cultures, customs, languages systems of communication, and widely varying conditions for clinical trials. A certain degree of generalization is impossible to avoid when discussing Africa, but this must always be balanced by a consideration that the region's diversity makes it impossible to predict every scenario for every country or subregion with respect to clinical trials. Therefore, it is important to obtain as much up-to-date information as possible on the locations of interest and seek advice from those with first-hand experience carrying out clinical studies in Africa. Those seeking to work in Africa must therefore conduct an in-depth and well-planned feasibility study before embarking on any project, to avoid potential problems and guard against complacency. 

Table 1.  United Nations definition of major areas and regions in Africa 						

The Declaration of Helsinki requires that control groups receive the “best” current treatment, not the “local” one. This shift in wording has profound implications.

Applied Clinical Trials-03-01-2005

Educating the Public: A Critical, Unmet Need

The Clinical Investigative Site Network

Training for the Real World

Baseline Balance and Valid Statistical Analyses: Common Misunderstandings

The Anatomy of Informed Consent

Approaching Africa

Pediatrics and Ethics Predominating in 2005

Communication and Clinical Trials

FDA Encourages Combo Product Development