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Institute of Medicine (US) Forum on Drug Discovery, Development, and Translation. Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary. Washington (DC): National Academies Press (US); 2010.

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Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary.

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3Challenges in Clinical Research

Cooperation among a diverse group of stakeholders—including research sponsors (industry, academia, government, nonprofit organizations, and patient advocates), clinical investigators, patients, payers, physicians, and regulators—is necessary in conducting a clinical trial today. Each stakeholder offers a different set of tools to support the essential components of a clinical trial. These resources form the infrastructure that currently supports clinical research in the United States. Time, money, personnel, materials (e.g., medical supplies), support systems (informatics as well as manpower), and a clear plan for completing the necessary steps in a trial are all part of the clinical research infrastructure. A number of workshop participants lamented that most clinical trials are conducted in a “one-off” manner.1 Significant time, energy, and money are spent on bringing the disparate resources for each trial together. Some workshop attendees suggested that efficiencies could be gained by streamlining the clinical trials infrastructure so that those investigating new research questions could quickly draw on resources already in place instead of reinventing the wheel for each trial.

This chapter summarizes workshop presentations and discussions focused on the challenges facing clinical research today. The first three challenges reflect broad, systemic issues in clinical research: (1) prioritizing of clinical research questions, (2) the divide between clinical research and clinical practice, and (3) the globalization of clinical trials. Issues of paying for clinical trials and the narrow incentives for practitioners to participate in clinical research are then discussed. Finally, the chapter turns to the challenges of a shrinking clinical research workforce, the difficulties of navigating administrative and regulatory requirements, and the recruitment and retention of patients.

PRIORITIZING OF CLINICAL RESEARCH QUESTIONS

Fewer than half of all the medical treatments delivered today are supported by evidence (IOM, 2007), yet the United States lacks a clear prioritization of the gaps in medical evidence and an allocation of clinical research resources to efficiently and effectively fill these evidence gaps. The federal government, industry, academic institutions, patient advocacy organizations, voluntary health organizations, and payers each have incentives to develop research questions that suit their unique interests. The value of a particular research effort is judged by stakeholders according to their own cost–benefit calculation. Reflecting the diversity of stakeholder value judgments, and in the absence of a broad national agenda, clinical trials are conducted in a “one-off,” narrowly focused fashion.

Because clinical trials are necessary to obtain regulatory approval in the United States, they are a high priority to companies. It was noted by a number of workshop participants that the prioritization of clinical research questions by companies seeking regulatory approval is distinctly different from the priorities of society in general, which may prioritize the comparison of two commonly used therapies. This divergence between the priorities of society and industry is notable as the nation discusses how to address the current gaps in clinical research and medical decision making.

As an example, in investigator-initiated research, academic investigators seek federal funding (primarily from the National Institutes of Health [NIH]) to conduct research they deem important to advancing science and/or medical practice. But James McNulty, Vice President of Peer Support for the Depression and Bipolar Support Alliance (DBSA), believes the NIH peer review process for research grants is inherently conservative and fails to reward innovative research into areas about which little is known. McNulty believes this conservative approach has contributed to serious gaps in knowledge in the area of mental health, specifically in schizophrenia, depression, and bipolar disorder. In terms of formulating relevant research hypotheses, the U.S. Department of Veterans Affairs (VA) was cited as one example of a health system that successfully engages practicing physicians in noting potential research questions that arise in the day-to-day care of patients. The VA Cooperative Studies Program works to ultimately take physicians’ questions into the clinical trial setting.

Industry-sponsored trials are conducted largely to gain U.S. Food and Drug Administration (FDA) approval to market a new drug or a previously approved drug for a new indication. Preapproval trials include a simple protocol (i.e., ask a limited number of questions) and test a drug in a highly selected patient group designed to provide the most robust evidence on the drug’s benefits and risks. Conversely, the federal government conducts large clinical trials to answer medical questions unrelated to gaining regulatory approval for a new drug or therapy. These studies can involve a wide range of patients and seek to answer a number of relevant clinical questions at once. Several presenters in the diabetes session of the workshop suggested that government-funded clinical trials for diabetes would not be conducted by industry or other sectors. New therapies for type 1 diabetes are often of limited interest to pharmaceutical companies because of the small patient population, whereas drugs for the exponentially larger type 2 diabetes population are avidly pursued.

The beginnings of a coordinated prioritization of research needs can be seen in the recent increased interest in comparative effectiveness research (CER). To enhance the ability of clinical research to generate knowledge that can better inform clinical practice, Congress included in the American Recovery and Reinvestment Act (ARRA) of 2009 an allocation of $1.1 billion for federal agencies (the Agency for Healthcare Research and Quality [AHRQ], NIH, and the Department of Health and Human Services [HHS]) to jumpstart the national CER effort. CER seeks to identify what works for which patients under what circumstances, providing evidence about the costs and benefits of different medical options. One-third of ARRA funds ($400 million) were designated as discretionary spending by the Secretary of HHS to accelerate CER efforts. The Institute of Medicine (IOM) was tasked with recommending national CER priorities to be supported with these discretionary funds and to guide the nation’s creation of a long-term, sustainable national CER enterprise.2 Recently enacted health care reform legislation (Patient Protection and Affordable Care Act passed in March 2010) created the Patient-Centered Outcomes Research Institute (PCORI)—a nonprofit institution positioned outside the federal government to define and execute comparative effectiveness research methods.

Several speakers and workshop participants raised questions about the ability of the current clinical trials system, which is already showing signs of strain, to absorb a substantial amount of the anticipated CER studies. Many voiced concern regarding the overall organization of clinical research in the United States: how it is prioritized, where it is conducted, who oversees it, how it is funded, who participates, and who staffs it. Presenters and participants also described the diminished capacity of the current clinical trials system. These observations, and proposed solutions, informed the discussion over the course of the 2-day workshop.

THE DIVIDE BETWEEN CLINICAL RESEARCH AND CLINICAL PRACTICE

Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research (CDER), identified bridging the divide between research and the clinical practice of medicine as one of the most critical needs facing the clinical research enterprise today. The limited involvement of community physicians in clinical research reduces physician referrals of patients to clinical research studies, as well as the total number of investigators available to conduct the research (see the discussion of narrow incentives for physician participation in clinical trials below). Furthermore, the findings of research conducted in academic medical centers rather than in community settings are less likely to be adopted by physicians in their daily practice. The poor rate of adoption of effective clinical practices is reflected in one study that examined adherence to 439 indicators of health care quality for 30 acute and chronic conditions and preventive care. Results indicated that American adults receive on average only 54.9 percent of recommended care (McGlynn et al., 2003).

Woodcock stressed that, to generate relevant research based in clinical practice, community practitioners must be actively involved in the clinical trial process. She suggested it is not surprising that the uptake of evidence-based practices is slow when practitioners are not engaged in the research that supports the changes. In many instances, the characteristics of the study population, their comorbidities and therapeutic regimens, and the setting and conditions under which the trial is conducted bear little resemblance to typical community practice. Indeed, the outcomes are often quite different as well. It is little wonder that community physicians may be hesitant to modify their treatment practices to reflect clinical findings developed in this manner. According to Woodcock, the divergence between physicians conducting research and those in community practice is one of the greatest barriers to successfully translating study results into clinical practice. She argued that, to develop a truly learning health care system capable of self-evaluation and improvement, the currently separate systems of clinical research and practice must converge.

Challenges Facing Investigators in Academic Health Centers

Woodcock discussed a number of important obstacles facing investigators conducting research using the current infrastructure. Clinical investigators, those who lead a research idea through the clinical trial process, face multiple small obstacles that together can appear insurmountable. These obstacles include locating funding, responding to multiple review cycles, obtaining Institutional Review Board (IRB) approvals, establishing clinical trial and material transfer agreements with sponsors and medical centers, recruiting patients, administering complicated informed consent agreements, securing protected research time from medical school departments, and completing large amounts of associated paperwork. As a result of these challenges, many who try their hand at clinical investigation drop out after their first trial. Especially in the case of investigator-initiated trials, where an individual’s idea and desire to explore a research question are the primary force behind the trial, the complex task of seeing a clinical trial through from beginning to end is making the clinical research career path unattractive for many young scientists and clinicians. Woodcock noted that in her experience, successful clinical investigators represent a select subset of clinicians—highly tenacious and persistent individuals with exceptional motivation to complete the clinical trial process.

According to Robert Califf, Vice Chancellor for Clinical Research and Director of the Duke Translational Medicine Institute, some of the challenges to participating in clinical research mentioned by clinical cardiovascular investigators include

  • the time and financial demands of clinical practice;
  • the overall shortage of cardiovascular specialists;
  • the increasing complexity of regulations;
  • the increasing complexity of contracts;
  • the lack of local supportive infrastructure;
  • inadequate research training;
  • less enjoyment from participation (e.g., increasing business aspects, contract research organization pressures); and
  • data collection challenges (medical records, reimbursement, quality control, pay for performance).

Califf noted that most of these challenges do not involve the actual conduct of a clinical trial and that many investigators say it is not difficult to get patients to participate in trials as long as the critical physician-patient interaction takes place. Investigators also cite the importance of support for research efforts from their home institution.

Challenges Confronting Community Physicians

Practitioners face a number of challenges to their involvement in clinical research. Busy patient practices and the associated billing and reporting requirements leave them with limited time for research. A further barrier is the lack of a supportive clinical research infrastructure, especially in the form of administrative and financial support. For practitioners who become engaged in running a clinical trial and recruiting patients, their financial reimbursement per patient can, in some cases, be less than they would receive from regular practice. In addition, there is a financial disincentive for physicians to refer their patients to clinical trials. Physicians who do so must often refer those patients away from their care; thus each patient referred represents a lost revenue stream.

Challenges Facing Patients

Patients also face challenges to participating in clinical research. Many workshop participants noted that patients often are unaware of the possibility of enrolling in a clinical trial. If they are aware of this opportunity, it is often difficult for them to locate a trial. Patients may reside far from study centers; even the largest multicenter trials can pose geographic challenges for those wishing to participate. Moreover, depending on the number of clinic visits required by the study protocol, significant travel and time costs may be associated with participation. In addition, trials designed with narrow eligibility criteria for participation purposely eliminate many patients who might have the disease being studied but are ineligible because of other characteristics (e.g., age, level of disease progression, exposure to certain medicines).

As noted, trials often require patients to temporarily leave the care of their regular doctor and receive services from unfamiliar providers. In addition to confronting potentially undesirable interruptions in care, it is understandably difficult for many patients to justify the physical and emotional strain of leaving their regular provider to volunteer for a clinical trial. If a patient reaches the point of enrolling in a clinical trial, the extensive paperwork associated with the informed consent process can be confusing and burdensome. As discussed later, informed consent forms are developed to meet legal requirements and can contribute to the confusion patients feel regarding the trial and what it entails. In addition, there is sometimes a mistrust of industry-sponsored trials among the public. These feelings of mistrust can further complicate the already difficult decision about whether to join a trial.

GLOBALIZATION OF CLINICAL TRIALS

The increasing trend toward conducting clinical trials outside the United States is an important consideration in discussing ways to improve the efficiency of trials. The number of patients enrolled in clinical trials is decreasing in the United States and increasing abroad. According to Woodcock, when development programs are conducted entirely outside the United States, the FDA questions the extent to which the results can be translated to U.S. clinical practice. The applicability of foreign trials results depends on the disease being studied and the state of current clinical practice in that area.

Califf suggested that the difficulties inherent in conducting clinical trials in the United States have contributed to the relative decline in U.S. clinical trials described in Chapter 2. Citing a recent paper that he coauthored, he noted that one-third of phase III trials for the 20 largest U.S. pharmaceutical companies are being conducted solely outside the United States (Glickman et al., 2009). For these same firms and studies, a majority of study sites (13,521 of 24,206) are abroad (Glickman et al., 2009). Califf stated that the situation is the same across study sponsors—NIH, industry, and academia all look to conduct trials internationally.

Califf suggested that globalization is a positive trend overall, one in which he and his home organization, the Duke Clinical Research Institute (DCRI), are engaged. However, the current situation in which clinical research is being sent abroad just to get trials completed is unsustainable. One reason for this situation is that clinical trials in a number of other countries cost less than they currently do in the United States (Table 3-1) (see also the discussion of costs below). If a large outcome trial requires enrolling tens of thousands of patients, for example, selecting trial sites in Russia or India instead of the United States can result in hundreds of millions of dollars in savings. The overall cost associated with gathering the necessary resources to conduct a clinical trial is an important factor in the choice of a trial site. For instance, physician salaries in a number of countries are lower than in the United States. In these countries, the charges to clinical trial sponsors for conducting a clinical trial with physician involvement are lower than they would be in the United States. Some also argue that clinical trials conducted outside of the United States are of higher quality because of better adherence to trial protocols and better patient follow-up.

TABLE 3-1. Global Research Costs: Relative Cost Indexes of Payments to Clinical Trial Sites.

TABLE 3-1

Global Research Costs: Relative Cost Indexes of Payments to Clinical Trial Sites.

THE COST OF CLINICAL TRIALS

Clinical trial costs can vary widely depending on the number of patients being sought, the number and location of research sites, the complexity of the trial protocol, and the reimbursement provided to investigators. The total cost can reach $300–$600 million to implement, conduct, and monitor a large, multicenter trial to completion. Table 3-2 outlines the various costs of an exemplar large, global clinical trial, which in this case add up to about $300 million.

TABLE 3-2. Breakdown of the Costs for a Large, Global Clinical Trial (14,000 patients, 300 sites).

TABLE 3-2

Breakdown of the Costs for a Large, Global Clinical Trial (14,000 patients, 300 sites).

Christopher Cannon, senior investigator in the Thrombolysis in Myocardial Infarction (TIMI) Study Group, stated that two clinical trials on which he is working cost a total of $600 million. To put this cost in perspective, it represents approximately half of the $1.1 billion allocated for comparative effectiveness research in the American Recovery and Reinvestment Act of 2009. According to Cannon, the exorbitant cost of clinical trials today points to the need to move toward simpler large trials that would study a broader population, include less data, and cost less overall.

The federal government funds a large portion of clinical research in the United States, primarily through NIH. In some cases, it has been estimated that NIH institutes pay research sites 20–40 percent less than the actual cost of conducting trials. Michael Lauer, Director of the Division of Cardiovascular Diseases, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, responded that to remedy the issue of appropriate NIH payments to research sites, the solution will likely involve a combination of increasing the amount of money paid by NIH to sites and decreasing the charges associated with conducting the research. Lauer further explained that because NIH’s funding is relatively flat, if research site payments are increased, an equivalent decrease in funding in other areas will be necessary. Given this zero-sum calculation, it will be politically difficult to increase payments for research sites. Lauer believes that simplifying trials could be most effective in reducing their cost. He suggested that good science comes from high-quality observations that are followed by focused experiments to test these observations. The trials that have had the greatest impact on clinical decision making and patient care have been simple (e.g., uncomplicated study protocols, short case report forms). Thus, if the research community could keep trials simple and large enough to answer the study question(s), costs could decrease, while the impact and relevance of the results would increase.

Workshop participants also discussed the inequality of NIH payments to research sites across the various NIH institutes. This variation has created a scenario in which some institutes that pay research sites more are seen as the “haves,” while those that pay less are seen as the “have-nots.” Judith Fradkin, Director of the Division of Diabetes, Endocrinology, and Metabolic Diseases in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health, noted that inconsistency across Clinical and Translational Science Awards (CTSA) institutions in the level of clinical trial support they provide makes it difficult for NIH to determine how its payments to research sites should be adjusted to take CTSA support into account.

NARROW INCENTIVES FOR PHYSICIAN PARTICIPATION IN CLINICAL RESEARCH

As discussed earlier, the current clinical research enterprise in the United States is largely separate from traditional clinical practice. In part because the United States does not have a nationalized health care system in which services are provided to all citizens through government-funded providers, clinical research takes place in various types of sites, frequently outside of the community-based, primary practice setting where most patients receive care. Moreover, as noted above, private practice physicians have disincentives to refer their patients to clinical trials. The fewer physicians are involved in developing and implementing clinical trials, the less scientific the practice of medicine will be. A number of workshop attendees suggested that a mechanism to adequately compensate physicians for referring patients to clinical trials could improve recruitment rates of U.S. patients. Making it easier for community-based physicians to participate actively in clinical trials could also have a positive effect on patient recruitment; enhance the engagement of the community in important research; and increase the chances that physicians will change their practice behavior based on research results they were involved in generating, thereby strengthening the trend toward evidence-based medicine in the United States. Workshop participants also suggested that, to encourage physician participation in clinical trials, the study questions and protocol should be designed in the context of clinical practice—that is, the procedures required by a trial protocol should be easily incorporated into practice.

It is also important to consider that the research questions clinical trials seek to answer reflect the incentives and interests of those developing the questions. In this respect, the capability of the health care system to act on trial results is part of the clinical research decision making process. For instance, Amir Kalali, Vice President, Medical and Scientific Services, and Global Therapeutic Team Leader CNS (central nervous system), at Quintiles Inc., explained that his company ran the two largest clinical trials testing the combination of psychotherapy and medication to treat depression. Despite scientific evidence for the benefits of psychotherapy, it has seen limited uptake. According to Kalali, this is because patients have limited access to psychotherapy as a medical treatment in the United States. Thus, the capability of the health care system to implement or act on research findings can be an important consideration in conducting clinical trials to test alternative treatments for a condition.

SHRINKING CLINICAL RESEARCH WORKFORCE

Research involving human subjects has become an increasingly complex environment in which to work and be successful. Thus, it is not surprising that, as noted in Chapter 1, the clinical investigator workforce is plagued by high turnover. Clifford Lane, Clinical Director, National Institute of Allergy and Infectious Diseases (NIAID), shared data from NIAID revealing the trend that fewer professionals are entering the research field than in the past. As Figure 3-1 indicates, the number of tenure-track principal investigators conducting research within the NIAID/NIH intramural program decreased from 74 in 2003 to 42 in 2008. While there was a slight increase to 53 tenure-track investigators in 2009, this number is still well below that in 2003.

FIGURE 3-1. While the number of senior NIAID/NIH tenured investigators is relatively stable, the number of NIAID/NIH tenure-track principal investigators is decreasing.

FIGURE 3-1

While the number of senior NIAID/NIH tenured investigators is relatively stable, the number of NIAID/NIH tenure-track principal investigators is decreasing. SOURCE: Lane, 2009. Courtesy of John Gallin, 2009 (unpublished).

The majority of phase III clinical trials are conducted by extramural researchers. However, trends in intramural NIH programs add to our general understanding of the issues and challenges facing investigators today. Lane commented that the overall decrease in intramural investigators is due in part to the fact that more researchers are turning to laboratory work because publishing results from this work is easier, and the difficulties of getting a clinical trial protocol approved can be avoided. Accordingly, NIAID has created a protocol development program to decrease the burden of regulatory and administrative requirements and optimize the use of existing clinical research tools. The program’s goal is to allow investigators to focus on their work as clinical scientists rather than having to serve as operations managers of a complex regulatory process. When investigators provide a robust scientific idea with a strong hypothesis, appropriate endpoints, and a sound study design, NIAID’s Office of the Clinical Director helps them navigate such regulatory issues as ethics review, technology transfer, safety concerns, and interactions with Institutional Review Boards (IRBs) and the FDA. This support can help investigators implement a trial successfully. In addition to principal investigators, multidisciplinary support staffs are necessary to complete a clinical trial successfully. Biostatisticians, epidemiologists, laboratory technicians, and administrative support personnel are just a few of the types of staff needed.

The importance of involving knowledgeable staff throughout a study was highlighted in a discussion of cardiovascular and depression clinical trials. Califf referred to the crucial role of a well-trained, intelligent data monitoring committee tasked with evaluating interim trial results. Data fluctuations revealed by interim trial monitoring require analysis but do not always indicate that a trial should be discontinued. For instance, when death is the primary outcome of a trial, data fluctuations may indicate an adverse effect on mortality of the treatment being studied or a regular clinical occurrence unrelated to the study drug. Califf noted that if it were not for a particularly well-informed data monitoring committee, the ISIS-2 (Second International Study of Infarct Survival) trial would have been most recently discontinued at 5,000 patients, with aspirin showing an adverse effect on mortality. William Potter, most recently Vice President of Translational Neuroscience, Neuroscience, Merck Research Labs, Merck & Co., Inc., indicated that in the depression studies in which he has been involved, interim data that indicate a possible adverse effect usually result in a trial’s being discontinued.

Because clinical trials are conducted in an ad hoc fashion, and study personnel of varying professional quality are recruited and trained anew at each site, inconsistencies in trial execution across sites are not unusual. Woodcock explained that the failure to execute a clinical trial successfully is often attributable in part to the fact that ensuring proper execution of a single trial is no one’s full-time job. The core activities of a clinical trial are largely supplemental responsibilities assigned to a variety of staff in addition to their full-time work.

Califf noted that clinical investigators often are unsupported by their academic institutions and are left largely to their own devices to design a trial and gather the necessary resources. The major reason for this lack of support, he suggested, is that clinical research is not widely respected among academics as a truly intellectual endeavor. Califf explained that, while investigators who are leading large, multisite trials predicted to have a major impact on clinical practice enjoy such respect, this is not the case for those conducting less visible work or just starting out in their research careers. A number of workshop participants expressed their support for rewarding academic researchers who conduct clinical trials. Early career development at the graduate and postgraduate levels could create incentives for more experts to enter the field of clinical research.

NEED TO NAVIGATE ADMINISTRATIVE AND REGULATORY REQUIREMENTS

The internal requirements of an academic institution, federal agency, or pharmaceutical company for reviewing multiple aspects of a clinical trial can significantly delay its initiation. In the case of an academic institution conducting a clinical trial for a pharmaceutical company, the internal review processes of both organizations are involved. In addition to such internal requirements, myriad federal and state regulatory requirements affect the conduct of clinical trials. Adhering to these many requirements is a significant challenge for investigators. Moreover, the delays incurred increase the time cost of a trial and decrease its overall efficiency. U.S. academic institutions typically take longer to navigate the approval process (i.e., from budget/contract to IRB approval) compared to private or academic institutions abroad. The protracted timeline to approve a clinical trial through U.S. institutions is one reason industry sponsors look outside the United States to initiate studies.

Institutional Review Board Approval

Gaining IRB approval is a requirement of the clinical trial process.3 Lane’s survey of intramural NIH investigators revealed that the top four barriers to clinical research are:

  • Ethical/IRB approval,
  • scientific review/protocol approval,
  • interaction with industry and issues with technology transfer, and
  • adequacy of resources.

Lane noted that there is often a lack of clarity among investigators regarding the roles and responsibilities of different oversight bodies. In focus groups with the investigators polled, it became clear that IRB missions can be difficult to interpret. Institutions have used IRBs for risk management above and beyond what is required for human subjects research, and included in their purview travel policies, conflicts of interest, and other management issues. Investigators often do not know or understand what the IRB expects of them, and the IRB decision-making process can be lacking in timeliness and accountability. Investigators reported that if the IRB process results in a request for changes to a trial, they often lack the resources to fulfill the request.

Paul Hébert, Editor-in-Chief of the Canadian Medical Association Journal (CMAJ) and critical care physician at the Ottawa Hospital, commented on the difficulties associated with IRB ethics review. A key concern is that IRBs are accountable only to their own institution and not to the greater public good. Hébert suggested that, to improve the regulatory system, IRBs should be held accountable to the community for the decisions they make. Moreover, decreasing the regulatory burden surrounding clinical trials does not need to be a zero-sum game. For example, decreasing the number of ethics reviews for a trial from 50 to 10 would be a substantial improvement over the current situation.

Carla Greenbaum, Director of the Benaroya Research Institute Diabetes Program and Clinical Research Center, shared her experiences and insights into the IRB process from the perspective of diabetes research. She noted that regulations vary by geographic location. Depending on location, for example, IRBs have different answers to the question of when research in children is appropriate, and they differ as well in how clinical research terms and phrases such as “minimal risk,” “slightly greater than minimal risk,” and “benefit” are defined. Geographic variation is also seen in IRB definitions of reportable adverse events, definitions of equipoise4 and whether a proposed study satisfies this requirement, and rules regarding whether permission can be granted for clinical trial samples to be retained indefinitely by the pharmaceutical sponsor versus NIDDK. Because multiple IRB approvals are required for most large, multisite clinical trials, these inconsistencies in IRB determinations and standards across the country complicate and delay the process of conducting a clinical trial and can inhibit the ability of investigators to implement the same trial protocol across all study sites—a critical factor for developing valid trial results.

Informed Consent

Informed consent refers to the process and documents associated with educating individuals on the details of a clinical trial and potentially gaining their consent to participate in the study.5 Obtaining informed consent from each subject in a clinical trial requires a significant amount of time. The informed consent process includes developing appropriately worded consent documents, discussing the documents and the clinical trial process with individual patients, obtaining the required patient signatures on the documents, and keeping track of the paperwork generated throughout the enrollment process.

As an example of the time and effort necessary to satisfy informed consent requirements, Greenbaum described a hypothetical scenario from her experience in diabetes research. A family consisting of two parents and four children, one with diabetes, decides to be screened for participation in a diabetes prevention study. The consent process for this family requires a total of 8 separate consent forms, each 6 pages long and requiring 16 signatures, plus 5 Health Information Portability and Accountability Act (HIPAA) forms. This paperwork is in addition to the extensive monitoring and compliance that accompany the consent process.

Greenbaum stressed the irrationality of the current situation in which an individual’s ability to participate in clinical research is dictated by geographic location. As a result of the level of local control exerted over clinical research, patients who frequent a hospital or medical center in one area of town may have access to certain clinical trials, whereas those at a hospital across town do not. For instance, some clinical trials organized through TrialNet are not approved at one institution in Greenbaum’s area because it is their policy that studies should not be conducted in children until the therapeutic approach has first been demonstrated to work in adults.

Protracted Time from Protocol Approval to Trial Activation

Administrative burdens are not always imposed on investigators by external laws and regulations. As Lane noted, many bottlenecks arise internally and are imposed by institutions that are home to the research workforce. In the government-sponsored Occluded Artery Trial (OAT), for instance, it took 3 years from the first NIH steering committee meeting to the start of the trial. Because clinical research relies on substantial human effort that incurs large labor costs, the timeline for a clinical trial affects overall cost. DiMasi and colleagues estimated that in 2000, the average cost to develop a new drug was $802 million, and time costs associated with the length of research and development accounted for half of this cost (DiMasi et al., 2003).

For the pharmaceutical industry, protracted timelines increase cost and reduce revenue as medications typically have a finite life before losing patent protection and creating an opportunity for generic competitors. Moreover, when a trial addresses a question important for medical practice, increasing the time it takes to obtain an answer can reduce the impact of the results. Musa Mayer, breast cancer survivor, advocate, and author (AdvancedBC.org), commented that if clinical trials are subject to significant delays, the standard of care can move on in the absence of phase III data. Thus, obstacles and delays in clinical trials move health care further away from evidence-based practice. Moreover, if the time lag is significant, the results of a lengthy, expensive trial may already have been rendered irrelevant by changes in clinical practice when they finally become available.

The one-off nature of trial organization, mentioned by a number of workshop participants as a major barrier to the efficient conduct of trials, is one factor leading to prolonged trial startup times. Years can elapse from the time researchers begin talking about a study idea to the point at which they assemble the appropriate investigators, develop collaborations, establish study sites, and initiate the trial.

Renzo Canetta, Vice President of Oncology Global Clinical Research, Bristol-Myers Squibb, provided an example of the internal administrative burdens faced by industry. Historically, Bristol-Myers Squibb has required 8 months, or 34 internal review cycles, to produce and activate a new study protocol. Recent efforts to improve the review cycle have been aimed at reducing this internal process to 150 days (5 months). Some individual institutions have exhibited greater flexibility and have been able to further streamline the protocol approval process. The University of Arkansas has a 70-day timeline for activating a new trial, while M.D. Anderson Cancer Center has a project under way (Project Zero Delay) to turn protocols around in 46 days, according to Canetta.

Case Report Forms

Collecting data for each participant in a clinical trial efficiently and accurately and according to the study objectives is essential for regulatory compliance, as well as the success of the research effort. The case report form (CRF) is the tool used by investigators to collect patient information throughout a clinical trial. Data Safety Monitoring Boards (DSMBs) are tasked with ongoing monitoring of the data collected in CRFs. A portion of the monitoring costs for a trial is directly linked to the complexity of the CRF developed for that trial. Complex CRFs with many data points are more expensive to monitor than simpler CRFs. A number of workshop participants noted that efforts to simplify CRFs so they include only the necessary, biologically relevant details of the trial could decrease trial costs.

Beyond the cost issue, the lack of standardized CRFs and trial procedures can create chaos in some study sites. Woodcock reflected on a recent meeting with the FDA and contract research organizations (CROs) in which the CROs openly discussed the monitoring of study sites. Among the problems they reported, many sites were not conducting critical study procedures correctly or entering all of the data required by the study protocol. According to Woodcock, poor understanding of the study protocol is a common problem in clinical trials and can lead to sloppy data collection and poor data quality. Califf suggested that expending resources and enrolling patients in a clinical trial that does not yield useful information could be considered unethical.

Clinical investigators may be trained to use multiple CRFs depending on the number of trials in which they participate. To reduce costs, Canetta suggested developing a standardized, electronic CRF for use across the research enterprise. Doing so would benefit all stakeholders—government and industry included—because it would help clinical investigators do their job more efficiently. Cooperative groups supported by the National Cancer Institute (NCI) are currently using standardized CRFs, and the Cancer Biomedical Informatics Grid (caBIG) online network is developing a library of standardized CRFs to be used throughout oncology trials.

RECRUITMENT AND RETENTION OF PATIENTS

A core function of a successful clinical trial is finding patients who fit the predetermined eligibility criteria and getting them to participate. Each disease area addressed during the workshop (cardiovascular disease, depression, cancer, and diabetes) has a unique patient base for clinical trials, and the issues that affect patient enrollment in trials can vary according to features of the disease. In addition, workshop participants identified challenges to patient recruitment that transcend disease status.

Patient Education

Mayer presented the results of a Harris Interactive Survey of 6,000 cancer patients that found that 85 percent were unaware that participation in clinical trials was even an option. Of the patients surveyed, 75 percent said that if participation in a clinical trial had been offered, they would have been receptive to the idea. Of those aware of clinical trials and offered the possibility of participation, 71 percent chose not to participate. However, almost all who participated were satisfied with the experience. Thus, according to these survey results, patients’ preconceived notions about trial participation could pose a barrier to clinical trial enrollment.

Greenbaum noted that the socioeconomic status of patients plays a role in whether they decide to enroll in clinical trials. In addition to income and education, patients’ access to health care services and the network of social support patients have to help them cope with their disease can affect their connection to the medical system and their interest in clinical research. As Mayer noted in her presentation, the online patient network she has developed for metastatic (advanced) breast cancer is composed primarily of younger, better educated, less diverse, and more affluent individuals as compared with the general population. Thus, higher socioeconomic status is associated with having the resources, knowledge, and motivation to seek information about a disease, including access to clinical trials.

Patient Recruitment

According to Woodcock, sites for clinical trials are frequently selected on the basis of where the investigators are located, as opposed to where the patients are, creating difficulties in patient recruitment. When patient recruitment is impeded, the trial is delayed, sometimes by years, until the number of patients required by the study protocol can be enrolled. Once a trial protocol has been activated, the recruitment of patients requires a significant amount of time and money. Canetta reported that the ability to recruit patients into a trial successfully is similar for the pharmaceutical industry and NCI. Regardless of the trial sponsor, recruitment of patients who meet the requirements of the protocol is difficult: in one study of 14 cancer centers approximately 50 percent of study sites failed to recruit a single patient (Durivage et al., 2009). Thus, patient enrollment can directly affect the number of trials that are completed.

Footnotes

1

The term “one-off” alludes to the current situation in which the necessary components of a trial (usually a single coordinating center and multiple research sites) are brought together for a discrete period of time and disbanded once the trial is completed.

2

A list of initial national priorities for CER recommended by the IOM in 2009 can be found at http://www​.iom.edu/Reports​/2009/ComparativeEffectivenessResearchPriorities.aspx.

3

An IRB is tasked with reviewing a clinical trial protocol to ensure that the study is conducted ethically and study participants are not likely to be harmed. An IRB can decide whether a clinical trial should continue as planned or changes should be made.

4

Equipoise is the point at which a rational, informed person has no preference between two (or more) available treatments (Lilford and Jackson, 1995). In clinical research, the ethical concept of equipoise is satisfied when genuine uncertainty exists as to the comparative therapeutic benefits of the therapies in each arm of a clinical trial.

5

The documents and conversations involved in the consent process explain the details of the clinical trial, including its purpose, the treatment procedures and schedule, potential risks and benefits, alternatives to participation, and the rights of participants (NCI, 2010).

Copyright © 2010, National Academy of Sciences.
Bookshelf ID: NBK50888

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