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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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2The State of Clinical Research in the United States: An Overview

The Institute of Medicine (IOM) reports To Err Is Human: Building a Safer Health System (IOM, 2000) and Crossing the Quality Chasm: A New Health System for the 21st Century (IOM, 2001a), focused the nation’s attention on concerns about the quality of health care in the United States. Since those reports were published, efforts have accelerated to develop a health care system that systematically measures and improves the quality of care delivered. Essential to such a system is a systematic approach for assessing which clinical approaches do and do not work and then ensuring that this knowledge is utilized in clinical decision making. This approach is what is often referred to as a learning health care system.

Many different kinds of evidence can inform the policies and practices of a health care system. Clinical trials, a type of clinical research, are one of the most robust sources of this knowledge. A number of workshop speakers from many backgrounds—clinical investigators, research sponsors, practitioners, and patients—expressed the view that the current clinical research enterprise1 in the United States is unable to produce the high-quality, timely, and actionable evidence needed to support a learning health care system. They identified numerous obstacles to producing this evidence, including the length of time and high financial cost involved in conducting clinical trials, delays associated with navigating the many regulatory and ethical requirements of studies involving human subjects (e.g., Institutional Review Board [IRB] approval), difficulties in recruiting and retaining the appropriate patient population, and the generally fragmented way clinical research is prioritized and undertaken to advance medical care in the United States.

As noted in Chapter 1, the workshop focused on the randomized controlled trial (RCT), the gold standard in clinical research. Many consider the RCT to be unsustainable as an approach to addressing the large number of research questions that need to be answered because of the time and expense involved. Yet alternative approaches have limitations with respect to producing high-quality data. Christopher Cannon, senior investigator in the Thrombolysis in Myocardial Infarction (TIMI) Study Group, for example, discussed the use of registries, which are large databases that provide extensive observational data on current clinical practice. He commented that while registry data are of good quality and less expensive to obtain compared with data from RCTs, confounding (i.e., why an individual received one therapy versus another) is a significant problem. Because it is difficult to attribute trends in registry data to particular therapies, registries do not provide the conclusive evidence necessary to change clinical practice. Instead, registries generate hypotheses that can then be tested in an RCT. Therefore, while patient registries and other research tools exist, the workshop focused primarily on RCTs.

Results of thousands of RCTs are published each year, yet clinical decision making frequently is not based on the evidence created by these results. A key issue informing the workshop discussions, then, was how RCTs can be conducted in an efficient, timely manner to answer all of the questions and meet all of the needs of a learning health care system. A logical first step in addressing this issue is to examine the clinical research enterprise as it operates in the United States today.

This chapter describes various aspects of clinical research in the United States, beginning with clinical research networks (CRNs). Research commissioned for the workshop from Ronald Krall, former Chief Medical Officer, GlaxoSmithKline, is then presented, addressing tools available for assessing clinical research in the United States; volume and type of clinical trials conducted; the clinical investigator workforce; and the overall capacity of the clinical research enterprise.

CLINICAL RESEARCH NETWORKS

CRNs have been developed to pool resources and expertise in conducting clinical research. They include clinical sites and investigators usually organized around a specific disease area and can be accessed by many different research stakeholders for the conduct of clinical research.

The National Institutes of Health’s (NIH’s) Roadmap for Medical Research points specifically to CRNs and their ability to rapidly conduct high-quality studies as a way to improve the efficiency and productivity of the clinical research enterprise. In this vein, NIH’s National Center for Research Resources (NCRR) manages the Inventory and Evaluation of Clinical Research Networks (IECRN) project to survey active networks and characterize best practices that could potentially be implemented in other networks or clinical trial settings. Although the exact structures vary, the NIH project defines a CRN as an organization of clinical sites and investigators that conducts or intends to conduct multiple collaborative research protocols. CRNs can carry out a number of different types of studies, including clinical trials, and the organization of sites and investigators can be formal or informal as long as the collaborative accomplishments of the group are clear. For instance, a group of researchers that conducts a single trial and subsequently disbands is not considered to be a network (NCRR, 2006).

By pooling the resources of multiple entities, CRNs can realize efficiencies in implementing and conducting clinical trials. They create a supportive infrastructure for investigators and can facilitate the rapid conduct of trials to answer important research questions. For instance, CRNs organized around a particular disease often have access to patients with that disease who can serve as study participants. The in-house scientific leadership of CRNs can also streamline the protocol development process and create uniformity in clinical trials across the network or disease area. When clinical trials from a particular network generate consistent results, this can also accelerate the drug development pipeline for the disease studied.

TOOLS FOR ASSESSING CLINICAL RESEARCH IN THE UNITED STATES2

Krall obtained information on the current state of clinical trials in the United States from various public and private sources. A key source was data on submissions to clinicaltrials.gov, a federally sponsored, publicly available registry of clinical trials. Information was also obtained from the Tufts Center for the Study of Drug Development, KMR Group, Citeline, and individual pharmaceutical companies. The Tufts Center and KMR collect data from pharmaceutical companies for the purpose of providing benchmarking data and proprietary analyses. Citeline is a proprietary data source that draws from a number of resources (literature, advertising, and clinicaltrials.gov) to create a comprehensive database of clinical research and the global investigator workforce.

Clinicaltrials.gov

The Food and Drug Administration Modernization Act (FDAMA) of 1997 mandated the creation of the clinicaltrials.gov registry for efficacy trials in serious and life-threatening conditions and interventions regulated by the FDA. Developed by NIH’s National Library of Medicine (NLM) in 2000, it allows interested parties to find information on both completed and ongoing clinical trials. The database includes federally and privately supported clinical trials, and study sponsors are responsible for submitting timely and accurate information about their studies.

The database registered a modest number of clinical trials in its initial years (Figure 2-1). A dramatic increase in trial registration came in 2005 in response to the newly introduced International Committee of Medical Journal Editors’ (ICMJE’s) requirement that studies published in their journals be registered in clinicaltrials.gov or other equivalent publicly available registries. The Food and Drug Administration Amendments Act (FDAAA) of 2007 created a legal requirement for the registration of trials of drugs, biologics, and devices, generating a modest increase in the registration of trials over what had been seen in 2005. Given the increasing number of trials registered on clinicaltrials.gov over time, the database encompasses a broad spectrum of research organized by study sponsor (industry, government, and nonprofit), disease and treatment being studied, and trial design.

FIGURE 2-1. Timeline reflecting the number of clinical trials registered on clinicaltrials.gov and regulatory changes affecting the database registration from 2001 to 2009.

FIGURE 2-1

Timeline reflecting the number of clinical trials registered on clinicaltrials.gov and regulatory changes affecting the database registration from 2001 to 2009. SOURCE: Krall, 2009. Reprinted with permission from Ronald Krall 2009.

Data Limitations

The information gathered by Krall to inform the workshop discussions of the state of the U.S. clinical research enterprise was not intended to provide an exhaustive analysis of the impact of every role and action of the broad range of research stakeholders involved. Rather, the goal was to highlight the productivity of one aspect of the clinical research enterprise—clinical trials. The data gathered reflect not the “effectiveness” of trials in terms of how well they answer the study questions, but how efficiently they are conducted. The commissioned research was designed to meet the needs of the workshop, however, the topics covered and issues raised by Krall’s analysis could be informative for other areas of the clinical research enterprise as well.

The data collected have some limitations. With respect to certain industry information, individual pharmaceutical company data can vary significantly depending on how the various elements and costs of clinical trials are measured. Also, although NLM reviews information submitted to the clinicaltrials.gov database, neither the accuracy of the data nor the scientific relevance of the study is guaranteed. Thus, while the information gathered on the number and type of clinical trials being conducted today is revealing, it would be incorrect to assume that it reflects the quality or relevance of those trials. Krall also noted that some types of clinical trials do not need to be reported to the database, and that there are concerns about the timeliness and accuracy of the data that are submitted. Variability in the reporting and classification of certain data elements in clinicaltrials.gov (e.g., drugs vs. biologics, phases of research, reporting no funding source, and currency of investigator site information) is another concern. Yet while clinicaltrials.gov is not without limitations, Krall suggested that its creation is undoubtedly a positive step toward developing a clearer picture of the state of clinical research in the United States.

VOLUME AND TYPE OF CLINICAL TRIALS CONDUCTED

In RCTs, investigators control which participants receive the study treatment by assigning them at random to a particular experimental study group. Observational, non-experimental studies occur in natural settings and involve no manipulation of the interventions or treatments study participants receive. Because RCTs were the focus of the workshop, observational studies were excluded from Krall’s analysis.

Krall reported that as of August 16, 2009, there were 10,974 ongoing, interventional clinical trials with at least one U.S. center. The 10,974 ongoing trials collectively are seeking to enroll 2.8 million subjects. As Figure 2-2 indicates, the majority of trials (59 percent) are testing drugs. A distant second and third to drug interventions are behavioral trials (10 percent) and those testing biologics (9 percent), respectively.

FIGURE 2-2. Percentage of the 10,974 ongoing clinical trials and 2.8 million study subjects being sought by intervention being tested.

FIGURE 2-2

Percentage of the 10,974 ongoing clinical trials and 2.8 million study subjects being sought by intervention being tested. SOURCE: Krall, 2009. Reprinted with permission from Ronald Krall 2009.

Clinical Trials by Phase of Research

The phase of clinical trials (i.e., phases 0-IV; see Chapter 1) is considered by some to be a marker of innovation, reported Krall. An analysis of clinical research by phase of experimental clinical trials can indicate the degree to which innovative new therapies are being developed and tested. It takes 10–15 years for a typical drug to be developed successfully from discovery to registration with the FDA. In the earlier phases of research, the chance of a drug reaching patients is small—approximately 1 in 10. In phase III research, however, the odds of registering a new product improve. About two-thirds of drugs that reach pivotal phase III trials will make it to the market (IOM, 2009c. 85).

To characterize trials by phase more precisely, Krall narrowed the focus of his research to trials for FDA-regulated interventions (drugs, biologics, devices, and dietary supplements). In these FDA-regulated categories, there are 8,386 trials recruiting 1.9 million subjects. As shown in Figure 2-3, among clinical trials for FDA-regulated products, phase II research is the largest category, followed closely by phase IV. Also referring to Figure 2-3, although there are larger numbers of phase II and III trials, phase III trials by design involve the largest number of participants; thus it makes sense that 52 percent of all subjects are enrolled in these pivotal trials.

FIGURE 2-3. Number of the 8,386 clinical trials involving FDA-regulated products and 1.9 million study subjects being sought for these trials by phase of research.

FIGURE 2-3

Number of the 8,386 clinical trials involving FDA-regulated products and 1.9 million study subjects being sought for these trials by phase of research. SOURCE: Krall, 2009. Reprinted with permission from Ronald Krall 2009.

Clinical Trials by Disease

Krall described ongoing clinical trials in the four disease areas of focus at the workshop—cardiovascular disease, depression, cancer, and diabetes. Figure 2-4 indicates that approximately half of the 10,974 trials being conducted today are in cancer; however, each such trial involves a relatively small number of participants. Figure 2-4 also reveals that cardiovascular disease trials are seeking more than 300,000 participants—10 percent of all clinical trial participants being recruited and far more than the number of participants sought for cancer, diabetes, or depression trials. Recruiting a large number of subjects per trial is a trademark of cardiovascular disease studies: on average, 275 patients are sought per cardiovascular trial, as compared with 20 patients per cancer trial, 70 patients per depression trial, and 100 per diabetes trial.

FIGURE 2-4. Number of the 10,974 ongoing clinical trials and 2.8 million study subjects being sought by disease being studied.

FIGURE 2-4

Number of the 10,974 ongoing clinical trials and 2.8 million study subjects being sought by disease being studied. NOTE: CV Disease = cardiovascular disease. SOURCE: Krall, 2009. Reprinted with permission from Ronald Krall 2009.

THE CLINICAL INVESTIGATOR WORKFORCE

Annual surveys from the Tufts Center for the Study of Drug Development indicate a consistently high turnover rate in the clinical investigator community. Investigators conducting a clinical trial to support a New Drug Application (NDA) or a change in labeling are required to complete FDA’s Form 1527. In 2007, 26,000 investigators registered this form with the FDA, 85 percent of whom participated in only one clinical trial. The issues facing clinical investigators were discussed throughout the workshop, and many participants echoed the theme of the Tufts data—it is difficult to conduct clinical trials in the United States and establish a career as a clinical investigator. While opportunities in clinical investigation can vary depending on whether or not an investigator is working in private practice or academia, for example, the challenges to successfully conducting a clinical trial in the United States are substantial. Making clinical investigation an attractive career option for academics and professionals was mentioned by a number of participants as an important component of any approach to improving the capacity of the clinical trials enterprise in the United States.

Globalization

In addition to high turnover, the U.S. clinical investigator workforce is subject to an absolute decrease in its ranks. While there has been an annual decline of 3.5 percent in U.S.-based investigators since 2001, there has been an increase in investigators outside the United States. Figure 2-5 reveals that investigators from the rest of the world increased steadily between 1997 and 2007, making up for the decline in North American investigators over the same period. As of 2007, U.S. investigators constituted 57 percent of the global investigator workforce, a decrease from approximately 85 percent in 1997. According to the Tufts data, there are an estimated 14,000 U.S. investigators, compared with an estimated 12,000 investigators outside the United States. Currently, 8.5 percent of investigators are from Central and Eastern Europe, 5.5 percent from Asia, and 5.5 percent from Latin America.

FIGURE 2-5. The proportion of clinical investigators from North America has decreased since 1997, while the proportion of investigators from Western Europe and the rest of the world has increased.

FIGURE 2-5

The proportion of clinical investigators from North America has decreased since 1997, while the proportion of investigators from Western Europe and the rest of the world has increased. SOURCE: Tufts Center for the Study of Drug Development. 2009. Impact (more...)

Finally, Krall noted the difference between the role of a clinical investigator (i.e., the person who establishes the hypotheses to test, designs the trial, analyses and reports the results) and that of the individual who finds patients to participate in a trial and collects information about them. The latter role is essential to the ability to carry out research and should be recognized, rewarded, and developed to a greater degree, according to Krall. Workshop presenters and participants echoed Krall’s sentiment later in the day by discussing the many different levels of staff, in addition to the principal investigator, that ultimately make a clinical trial successful.

CAPACITY OF THE CLINICAL RESEARCH ENTERPRISE

KMR data from 2006 for the 15 largest pharmaceutical companies show that the majority of patient visits associated with an industry-sponsored clinical trial occur outside the United States. According to Krall, this statistic speaks to the costs and difficulty associated with conducting clinical research in the United States. In terms of cost-effectiveness, 860 patient visits occur in the United States per $1 million spent on clinical operations, whereas for the same cost, 902 patient visits occur outside of the United States. Thus, by the measure of cost per patient visit, U.S.-based clinical trials are not as cost-effective as those in the rest of the world. Krall urged caution in interpreting these data, however, given the high degree of variability among pharmaceutical companies in patient visit and cost measures.

U.S. investigators enroll two-thirds as many subjects into clinical trials as investigators in the rest of the world. Among U.S. investigators participating in a clinical trial, 27 percent fail to enroll any subjects, compared with 19 percent of investigators elsewhere. Investigator performance in the United States and the rest of the world is similar in that 75 percent of investigators fail to enroll the target number of subjects; also, 90 percent of all clinical trials worldwide fail to enroll patients within the target amount of time and must extend their enrollment period. Krall commented that these data on patient enrollment are from one pharmaceutical company but that, based on his industry experience and conversations with colleagues from other companies, he believes the data are generally consistent with the pharmaceutical industry as a whole.

According to clinicaltrials.gov data, clinical trials today call for the enrollment of 1 in every 200 Americans as study participants. Because this is such a remarkable undertaking, Krall questioned whether this high level of human participation is being put to the best use possible—that is, are the right questions being asked through the thousands of clinical trials being conducted today?

Footnotes

1

The clinical research enterprise is a broad term that encompasses the full spectrum of clinical research and its applications. It includes early-stage, laboratory research and the processes, institutions, and individuals that eventually apply research to patient care (IOM, 2002).

2

The remainder of this chapter is based on the presentation of Dr. Krall.

Copyright © 2010, National Academy of Sciences.
Bookshelf ID: NBK50886

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