Appendix D

Discussion Paper1

The Clinical Trials Enterprise in the United States:
A Call for Disruptive Innovation

Robert M. Califf, Duke University Medical Center; Gary L. Filerman, Atlas Health Foundation; Richard K. Murray, Merck & Co., Inc.; and Michael Rosenblatt, Merck & Co., Inc.2

INTRODUCTION

Over the past decade, the symbiotic relationship between the clinical trials enterprise (CTE) and the health care delivery system has been subject to increasing amounts of stress. During this period, the CTE has primarily focused on process improvement, seeking to create and maintain procedures and data systems that can satisfy a regulatory environment concerned with specific research procedures. These efforts have driven up the cost of research and left the CTE increasingly out of sync with the health care delivery system.

At the same time, there have been many significant changes in the health care delivery system, changes largely concerned with organization, quality improvement, operational efficiency, and error reduction

______________________

1 The views expressed in this discussion paper are those of the authors and not necessarily of the authors’ organizations or of the Institute of Medicine. The paper is intended to help inform and stimulate discussion. It has not been subjected to the review procedures of the Institute of Medicine and is not a report of the Institute of Medicine or of the National Research Council.

2 Participants in the activities of the IOM Forum on Drug Discovery, Development, and Translation. This discussion paper was presented in draft form at the Forum’s November 2011 workshop, Envisioning a Transformed Clinical Trials Enterprise in the United States: Establishing an Agenda for 2020, and finalized by the authors following the workshop. The authors would like to thank David Davis, Jeffrey Drazen, Ronald Krall, Samuel Nussbaum, Neil Weissman, and Marcus Wilson for their comments and suggestions on draft versions of this paper.



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Appendix D Discussion Paper1 The Clinical Trials Enterprise in the United States: A Call for Disruptive Innovation Robert M. Califf, Duke University Medical Center; Gary L. Filerman, Atlas Health Foundation; Richard K. Murray, Merck & Co., Inc.; and Michael Rosenblatt, Merck & Co., Inc.2 INTRODUCTION Over the past decade, the symbiotic relationship between the clinical trials enterprise (CTE) and the health care delivery system has been sub - ject to increasing amounts of stress. During this period, the CTE has pri- marily focused on process improvement, seeking to create and maintain procedures and data systems that can satisfy a regulatory environment concerned with specific research procedures. These efforts have driven up the cost of research and left the CTE increasingly out of sync with the health care delivery system. At the same time, there have been many significant changes in the health care delivery system, changes largely concerned with organiza - tion, quality improvement, operational efficiency, and error reduction 1 The views expressed in this discussion paper are those of the authors and not necessarily of the authors’ organizations or of the Institute of Medicine. The paper is intended to help inform and stimulate discussion. It has not been subjected to the review procedures of the Institute of Medicine and is not a report of the Institute of Medicine or of the National Research Council. 2 Participants in the activities of the IOM Forum on Drug Discovery, Development, and Translation. This discussion paper was presented in draft form at the Forum’s November 2011 workshop, Envisioning a Transformed Clinical Trials Enterprise in the United States: Establishing an Agenda for 2020, and finalized by the authors following the workshop. The authors would like to thank David Davis, Jeffrey Drazen, Ronald Krall, Samuel Nussbaum, Neil Weissman, and Marcus Wilson for their comments and suggestions on draft versions of this paper. 133

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134 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE and patient safety. Despite significant rhetoric (particularly in the United States) about “learning health systems” (Institute of Medicine [IOM], 2007), the CTE and the health care delivery system have continued to diverge. This situation is undesirable both because research done within such a partitioned, parallel system may not be broadly generalizable and because the cost of maintaining parallel systems limits our ability to address critical gaps in knowledge. The end result of the widening separation between research and health care delivery will be a serious deficit in new knowledge about the ben- efits and risks of specific drugs and devices in medical practice at a time when biological knowledge is expanding exponentially (see Figure 1) and warnings about the unsustainability of the system continue to escalate (IOM, 2008). This systemic divergence, in turn, deprives providers of reli- able evidence upon which to base their practices, deprives patients of the expected return on research investments in science and medicine, and deprives policy makers of a rational basis for choosing one course of action over another. The scope and pace of change in the overall health system will only increase as we enter the next decade, exacerbating the undesirable sepa- ration of research and practice. There is thus an urgent need to develop policies that will mitigate current stresses and increase CTE efficiency and effectiveness by expeditiously forming a deliberate plan to align the CTE and the emerging health care delivery system. Such an effort will require a new assertion of the societal values that underlie the CTE, a clarification of the objectives of such a plan, and accommodations on the parts of both the CTE and the health care delivery system to accomplish those objectives. A decade ago, the National Institutes of Health (NIH) embarked upon a major effort to reshape the future of biomedical research. This framework for change, called the NIH Roadmap (Zerhouni, 2003), articu- lated a vision for clinical research in which each of more than 300 million Americans would have his or her own electronic health record (EHR). If individuals so chose (assuming appropriate privacy and confidentiality protections), the information in these EHRs could be used for research, and patients and their families would be joined together in networks that could answer critical questions about prevention and treatment. The fabric of constantly-accruing data would form the basis of a learning health system in which randomized trials could be performed by inserting randomization into the routine delivery of health care. This revolutionary approach would allow the rapid and definitive development of evidence at a relatively low cost. Although this vision from a decade ago has not been achieved, much of it is within reach by 2020. Consolidations of service delivery and insur- ance organizations are changing the context of practice. Technological

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135 APPENDIX D limitations are being overcome, disease-oriented networks and voluntary health organizations are evolving, and modern medical informatics is enabling the aggregation, classification, indexing, and analysis of infor- mation in volumes that were unimaginable a decade ago. Unfortunately, at the same time these tools are emerging, the CTE is increasingly being cordoned off from the rapidly-evolving, information-intensive world of medical practice. This paper provides a roadmap for integrating the clini - cal trials and health care delivery systems in ways that will improve the efficiency and effectiveness of both. Current Status of the Clinical Trials Enterprise The passage of the Food and Drug Administration (FDA) Amend- ment Act in 2007 (FDA, 2007) mandated the registration of most clinical trials involving medical products approved for use in the United States. The resulting increase in the number of trials registered and the quality of the information provided to entities such as ClinicalTrials.gov has afforded us a new opportunity to assess the state of the overall CTE. When we examine these data, several significant patterns are mani- fest. First, the vast majority of clinical research comprises tiny trials per- formed on small numbers of patients (62 percent of studies plan to accrue fewer than 100 participants; 96 percent have a projected accrual of <1,000) (Califf et al. [in review]). Second, the majority of trials are sponsored by academic health centers (AHCs) and are focused on disease mecha - nisms, or are phase 1 and 2 studies sponsored by industry. The majority of research participants, however, are enrolled in industry-sponsored phase 2, 3, or 4 trials that are fewer but larger in size and increasingly globalized (Glickman et al., 2009). Third, relatively few trials are asking questions that directly address critical decision points in clinical practice. A typical clinical trial today depends on the recruitment of investi- gators who, in turn, recruit trial participants and oversee the conduct of the research protocol. There is, however, no assurance that the recruited participants are sufficiently representative of broader populations to allow generalization of trial results. Further, these trials are often con- ducted at professional clinical trial sites that produce clean data, but at the cost of divorcing the trial from clinical care. At the same time, we now have multiple integrated health systems, including not only well-known health management organizations (HMOs) and the Department of Vet - erans Affairs (VA) system, but also numerous integrated health systems (IHSs) that possess data warehouses capable of supporting the selection of research participants in a much more systematic fashion. These problems are compounded by a decline in the number of U.S. investigators, while at the same time the total number of clinical

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136 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE trials worldwide has nearly doubled in the last decade (Getz, 2005). This decline also coincides with a rapid expansion of the offshoring of clinical research activities, a particularly worrisome trend (Califf, 2011; Kim et al., 2011). In this context, “offshoring” of trials refers to the movement of research away from the United States purely because of the excess cost and difficulty of conducting research domestically, including long start-up times, slow recruitment, and high rates of non-adherence and withdrawal of consent. Offshoring is not a synonym for globalization, which allows many countries and cultures to participate in research and which we regard as a positive development for all diseases. Globalization of clini - cal research can be particularly beneficial when the research addresses neglected diseases (Bollyky, 2011) or major chronic diseases that may have a different outcome or treatment effect with different genetic backgrounds or patterns of clinical care than those found in the United States. Offshoring is a concern because it diminishes synergies between basic and clinical research that are vital to translational research, and because it weakens the interface with industry that speeds advances in drugs and devices made available to the American public. Furthermore, research performed in different populations or under different conditions may not be fully generalizable unless particular care is taken. And while the NIH Roadmap vision calls for a seamless and efficient integration of research and practice, in reality we see that the focus on efficiency in practice has led to the view that research is a source of additional expense and burden - some administrative and regulatory commitments (Califf, 2009). At the same time, when clinical research is not integrated with practice, its focus on efficiency in isolation from other factors distances it further from the environment crucial to producing generalizable results. PART I: ORGANIZATION OF HEALTH SERVICES IN 2020 This section describes our vision of the health systems of 2020. In health services, demography is destiny. At the largest scale, demo - graphic patterns drive a substantial portion of the demand for services. Less obvious, however, is the manner in which American demography mandates the organization of the services that respond to that demand, how and by whom services are paid for, and who provides the services. The U.S. Census Bureau estimates that by 2020 there will be more than 341 million Americans, of whom nearly 55 million (16 percent) will be 65 years of age or older. Among these will be an estimated 135,000 cen - tenarians (U.S. Census Bureau, 2008). The population of the country as a whole will be ethnically diverse; this will be especially true for those under the age of 20. Most patient and provider interactions will take place in the context of managing chronic conditions—chiefly depres -

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137 APPENDIX D sion, cancers, cardiovascular disease, diabetes, arthritis, asthma, and Alzheimer’s disease. Throughout their lifetimes, most Americans will either be enrolled in or anticipating enrollment in an IHS that will provide all or nearly all of their health care. By 2020, there will be substantial but uneven progress toward establishing the IHS as the dominant form of health care organiza- tion, particularly in urban settings. Elements of IHS implementation will be in place in most communities. The typical IHS is community hospital–centered and oriented toward providing primary care. Integration is driven by enrollment, bundled payment, EHRs, and standardized health care. It serves an enrolled (i.e., defined) population. It is further defined by the scope of and coordi - nation among the comprehensive services that comprise its network, including directly owned or contracted multi-specialty medical group practices, ambulatory care centers (including imaging, walk-in “retail” clinics, employee wellness facilities, rehabilitation centers, etc.), home health agencies, nursing homes, extended care facilities, and hospital- and home-based hospice services within its primary service area. Most IHSs are affiliated with local public health departments and community health centers. All IHSs have collaborative agreements with AHCs for education and research support. The IHS and/or affiliated group practices serves as the locus of medical homes and accountable care organizations. Integrated health care organizations and their affiliated service organi- zations either employ or contract with a substantial majority of health care providers, including physicians, nurses, advanced-practice nurses, physi- cian assistants, clinical social workers, and psychologists. Pharmacists are engaged in provider and patient counseling across the system. Although IHSs provide comprehensive data, patients/customers and their families switch from one IHS to another, with the result that interoperability is an indispensible characteristic of any viable data system. Health care professionals have a strong sense of identity with the IHS, which is the focus of much of their professional activity. There is also a high degree of alignment between system objectives and professional expectations and roles that is achieved through recruitment, position and role description, promotion, remuneration, and incentives. The objective of implementing a culture of patient-centered care through the optimal deployment of appropriate competencies is reflected in the organization of teams that respond to the patient’s changing needs. The EHR can be characterized as the clinical and administrative core of the IHS. It is designed to meet both administrative and clinical needs and employs nationally standardized interoperability and nomenclature. The scope of “meaningful use” of EHR technology has been expanded to embrace and incentivize research. Empowered by virtualization, the

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138 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE EHR is designed to enable preventive, clinical, and supportive services throughout an enrollee’s life. The development and maturation of EHR technologies promise to make practicable the application of genetic information to medical practice. The EHR is also designed to provide the continuous aggregate data that are essential for assessing the health of the enrolled population, continually improving the quality of care throughout the IHS, and supporting clinical research and professional education. Of paramount importance, however, is the fact that the EHR enables the system, the provider, and the researcher to follow up with the patient over time. Large population-based real-time evidence is the prod - uct of aggregated health system databases. Randomization is facilitated through super computer–based virtually-integrated information systems that merge administrative and clinical data from multiple sources. The virtually-integrated networks, spanning providers and payers, make it possible to enroll individuals in trials and to follow them going forward. The magnitude of the databases and the power of the tools make pos- sible analyses that are responsive to the cultural diversity of the study populations. The EHR is first initiated when the patient enrolls or enters any of the component organizations and services. Integrated with web-based mobile technology, the EHR “follows” the patient home, issuing reminders and monitoring compliance, as well as capturing incidents and wellness indi - cators (FasterCures, 2005). In 2020, there is wide public recognition that research is an integral component of community-based practice. The basic compact between the patient and the provider community is that every patient is a potential contributor to research. It is assumed that the patient record may be used for research in a de-identified data system. The patient-oriented part of the EHR is owned by the patient and is acces- sible only by the patient or by family members and providers to whom the patient grants access. Special permission is required to use such infor- mation in research projects that could potentially identify the individual. The maintenance and improvement of professional competence is an objective of all IHSs and defines them, in the terms of an earlier IOM report, as “learning health systems” (IOM, 2011a). The formal relation - ships with providers across all participating settings as well as the aggre - gate clinical and administrative data generated by the EHR provide the foundation for feedback and for rigorous and sustained continuing educa- tion. Every health care delivery site is a learning site, providing continu - ing health education (CHE) that includes point-of-care reminders, links to clinical practice guidelines, and other online resources. This is in addition to traditional CME activities that are at once targeted to the objectives of the IHS and to the need for education where it is most effective—the point of patient engagement.

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139 APPENDIX D In 2020 the professional specialty societies, providing leadership for knowledge, are one of the most influential factors moving research par- ticipation into the definition of successful practice. Research participation is highlighted and promoted in the educational programs, publications, and recogitions of the societies. The societies support research directly by maintaining registries of clinical experience to which they have unique access and through fellowships that enable community-based practitioners to gain research experience. Board-certification requirements recognize research and particularly translation skills. Academic health centers are integrally related to IHSs. The missions and priorities of AHCs have been clarified to distinguish between those with a substantial investment in basic and translational research, and those that are primarily focused on education and service. The more comprehensive of the former have been designated as academic health science systems (AHSSs) (Dzau, et al. 2010). All AHSSs are organized to serve as research sites for enrollment in observational studies and inter- ventional trials. All IHSs are affiliated with an AHC, which could be an AHSS, which serves them as a resource for education and clinical research through an affiliated IHS office or department. In most cases, the affili - ated academic centers have access to the IHS databases for the purpose of maintaining registries and conducting collaborative projects. A fundamental element undergirding mature electronic health and medical records is the application of an ontology that permits the same terms to be used for describing clinical phenomena and for billing; they also form the basis for quality measurement and for providing adjust - ments for severity of illness when efficiency measures are assessed. These same terms will also constitute the fundamental “vocabulary” for both observational research databases and randomized controlled trials (RCTs). When needed, additional data elements are added for more detailed investigation and randomization is applied to the record. While the nation has yet to reach this envisioned state of health system integra- tion and effective use of the EHR, the implementation of national health care reform legislation and the efforts of organizations to display their accountability for health care outcomes and costs will likely bring us closer to this stated vision. PART II: THE FUTURE OF CLINICAL RESEARCH Controlled clinical trials are the essential cornerstone of modern evidence-based medical care and health practice. Although multiple types of information are needed to fully inform practice, the interventional clini- cal trial (ICT) plays a particularly critical role. When we view scientific studies as a continuum, we see that they are translated into treatments

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140 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE through a series of steps, beginning with preclinical research that evolves into early-phase clinical trials designed to assess safety and demonstrate proof-of-concept for on-target and off-target effects. Successful interven - tions (drugs, devices, behavioral strategies) are next evaluated using con - trolled trials to determine whether the balance of risks and benefits merits the marketing of the technology or intervention. When such studies are robust, practice guidelines can be developed to guide clinical decision making; when they are definitive, guidelines can be distilled into per- formance measures to assess the quality of practice. At the heart of this paradigm is the measurement of process and outcomes, combined with the use of the measurement system to guide continuous education of practitioners and to assess therapeutic deficits that require new interven - tions to overcome. When the effects of an intervention are modest (as is typically the case), randomization provides the most reliable method for determin- ing the true effect of the intervention compared with an alternative. The first known description of an interventional trial is Lind’s 18th-century account of using fruit to combat scurvy (Lind, 1753). Following Fisher’s pioneering demonstration of randomization in a series of agricultural experiments in the 1920s (Fisher, 1926), the first randomized clinical trial was conducted by the British Medical Research Council to evaluate streptomycin for tuberculosis in 1946 (Medical Research Council, 1948). In the 1960s the NIH became the dominant force in developing clini- cal trials methodologies (Coronary Drug Project Research Group, 1973) and in 1962, following passage of the Kefauver-Harris Drug Amend- ments, the FDA took the position that efficacy must be established prior to the marketing of drugs (FDA, 2006). As a result of these developments, the RCT was adopted as the standard by which efficacy was determined. Soon, regulatory agencies in other countries joined in, and the majority of research participants were enrolled in trials sponsored by industry and intended to develop or evaluate drugs or devices. In the 1990s the CTE globalized, spurred by the simultaneous expansion of medical technology development together with the global need to understand the effects of health interventions (as well as any associated economic and scientific benefits) in all societies. A major problem in the field of clinical research is the current absence of a standard ontology that adequately encompasses its activities, render- ing it difficult to characterize the state of the enterprise. Common metrics must be based on common definitions so that valid comparisons can be made and policy decisions are based on solid evidence. This prob - lem is illustrated by the multiple definitions of the term “clinical trial.” For the purposes of this report, we have adopted the definition used by the ClinicalTrials.gov registry: “biomedical or health-related research

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141 APPENDIX D studies in human beings that follow a pre-defined protocol. Interven- tional studies are those in which the research subjects are assigned by the investigator to a treatment or other intervention, and their outcomes are measured” (National Institutes of Health, 2007). This broad definition thus includes nonrandomized interventions but excludes registries that simply measure practice, as well as research confined to databases. As the clinical research ontology develops, better classification will be key to accurately measuring the progress of the enterprise by comparing the same types of studies and methods over time. Currently, more than 330 clinical trials are registered every week with the ClinicalTrials.gov registry, which now contains data on more than 110,000 studies. In reviewing data from ClinicalTrials.gov, the CTE is revealed as highly complex, with research studies fulfilling a wide variety of purposes (see Table 1). As we noted earlier, the majority of clinical trials are small, conducted in AHSSs, and sponsored either by the federal government (typically through the NIH) or funded internally by the academic organization. However, the vast majority of patients are enrolled in industry-sponsored trials, due to academic trials’ small size and the fact that they are typically not intended to inform practice; rather, academic trials are oriented toward elucidating biological mechanisms or developing pilot data. However, industry resembles academic research in one respect: it conducts many more small, early-phase trials than it does large studies intended to inform practice. While trials are conducted in all disease areas, the distribution is dominated by cancer, cardiovascular medicine, and mental health. Both across disease areas and within spe - cialty areas, it is clear that trial portfolios do not match public health or community medical practice needs in terms of either magnitude or urgency. Historically, the United States has been a dominant presence in clini - cal research, but there is growing concern that the enterprise is in decline. There is ample evidence that U.S. trials are becoming more expensive (DeVol et al., 2011). Worse, 90 percent fail to meet enrollment goals, and additional evidence points to disillusionment among American inves- tigators (Getz, 2005). The rate of attrition among U.S. investigators is increasing, even among experienced researchers with strong track records of productivity, while 45 percent of first-time investigators abandon the field after their first trial. The system has become so inefficient that even the NIH is offshoring clinical trials at a substantial rate (Califf, 2011; Kim et al., 2011), using taxpayer funding to conduct trials in countries with less expensive and more efficient CTEs, despite concerns about generaliz - ability as noted above. While the CTE is in decline in the United States, the need for trials, paradoxically, is increasingly well-recognized. Recent reports indicate

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142 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE that fewer than 15 percent of major recommendations in clinical practice guidelines in infectious disease (Lee and Vielemeyer, 2011) and cardio- vascular disease (Tricoci et al., 2009) are based on solid evidence. Recent failures to perform proper trials have led to public health hazards after drugs were developed and marketed without proper supporting evi- dence. The wide-scale use of antiarrhythmic drugs provides a sentinel example: the CAST Trial (Pratt and Moye, 1990) demonstrated that a treatment that was being used to prevent death was actually causing excess mortality. Similarly, hormone replacement therapy (HRT) was thought to reduce cardiovascular disease until the HERS Trial (Hulley et al., 1998) and the Women’s Health Initiative (Rossouw et al., 2002) demonstrated an excess hazard for cardiovascular events with HRT. Most recently, high-dose erythropoietin appeared to provide substantial ben- efit in anemia related to renal failure and cancer, and clinical practice guidelines touted its use. But when controlled trials were finally done, high-dose erythropoiesis-stimulating agents were found to cause excess cardiovascular events (Bennet et al., 2008; FDA, 2011; Pfeffer et al., 2009; Singh et al., 2006). Never has the need for properly controlled interven- tional trials been so clear. The decline of the U.S. CTE has been noticed by other countries, which are moving rapidly to fill in the gap. The United Kingdom has recently published a national strategy aimed at gaining a larger market share of clinical trials (The Academy of Medical Sciences, 2011) and has made research a primary mission of the National Health Service. Canada has developed a national plan (Canadian Institutes of Health Research, 2011) and China and India are focused on increasing their participation in clinical trials (Gupta and Padhy, 2011; Jia, 2005). At the same time, many countries are providing incentives for industry to locate clinical trials in their countries. As we note above, we regard globalization of clinical trials as an important positive trend, but the motivating factor should be to provide population- and culture-specific medical evidence to inform local practice. If globalization takes place merely because the United States cannot enroll research participants or has priced itself out of the market, the net result may prove negative. Having countries assume a low-cost vendor status in circumstances where their own populations may not benefit from the research is also troubling from an ethical perspective. Substantial evidence indicates that the fundamental problem is not rooted in the attitudes of the U.S. public. Although there appears to be variation among socioeconomic and ethnic groups, the public in general places high value on both research in general and clinical research in par- ticular. The majority of Americans report that they would either certainly or most likely participate in research if asked (Getz, 2011). Additionally, an

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143 APPENDIX D overwhelming majority of those who participate in clinical trials find them to be a positive experience and report that they would do it again. Rather, the problem is not with people but with the health care system—patients are not being asked to participate and many barriers exist (IOM, 2011b). Because of these challenges, we believe that the CTE can and must be improved and integrated with the evolving health care delivery sys - tem as part of an essential evolution toward the learning health system envisioned by the IOM (2007). The CTE can be envisioned as four over- lapping enterprises, which we refer to as “laboratories” to emphasize the vast needs that remain to be addressed by the continuing evolution of the entire system. These laboratories share a common fabric of methods, but are different enough that specialized training and education will be needed, intensive methodological work will be required, and investments must be made to produce results that can revolutionize our understand- ing of how to better prevent, manage, and treat disease. The Innovator’s Lab The majority of clinical trials will continue to enroll small numbers of research participants to address biological hypotheses, to develop initial evidence about the mechanisms of action of drugs, devices, and other interventions, or to develop preliminary evidence of their risk–benefit pro- file. We believe that the world of phase 1 units and academic studies must be combined into a much more effective approach to human systems biol- ogy. This new system should be highly networked, enabling researchers to leverage major advances in genetics, genomics, and biomarkers. Because studies of biological mechanisms and early studies of new therapies require intensive measurements in human volunteers, these studies should be performed in an environment separate from the health care delivery system. Recent evaluation has implicated both a failure to fully engage the biological target of therapy as well as “off-target” effects in the high rate of attrition characteristic of early-phase trials. Also, when late-phase failures are evaluated, off-target effects frequently emerge as the cause. Systems biological measurements, in which multiple biological outcomes can be monitored simultaneously, promise better characteriza- tion of on-target effects as well as better identification of off-target effects. The environment for this type of research should be intensive in terms of highly qualified staff and sophisticated data-management capabilities. Because the studied populations will either be 1) normal volunteers or 2) patients with a disease of interest exposed to a new drug or device and/ or undergoing intensive measurement, the most effective environment will likely be found within a hospital with advanced emergency care, imaging, and data capabilities.

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150 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE presentations within the system and provide a basis for communications to the community, enhancing the message that their health system is a learning organization. PART IV: IMPLEMENTING THE RESEARCH AGENDA This vision of disruptive innovation, one that is necessary to trans- form the challenged 2011 CTE into the robust CTE of 2020, generates researchable questions to be addressed with alacrity by the health services community. These questions reside largely in the domain of health ser- vices research (HSR), which has been defined as “a multidisciplinary field of inquiry, both basic and applied, that examines the use, costs, quality, accessibility, delivery, organization, financing and outcomes of health care services” (IOM, 1995). As implementation of the integrated community-based health system model proceeds, the following questions are examples of the research agenda that is called for: • hat are successful cases of securing health system cultural change W and system-wide buy-in? • hat are the specific impediments to change in organizational W culture? • ow have each of the impediments been managed? H • hat are the financing and costing alternatives and their W implications? • ow have the systems that have adopted a research agenda orga- H nized to implement it? • hat are the characteristics of community medical groups and W practitioners that participate actively in clinical research? • hat approaches to enlisting practitioner participation are most W successful? • hat approaches to securing trial enrollment and participant W retention are most successful in the community practice setting? • ow have community-based research programs succeeded in H engaging culturally and linguistically diverse populations? • ow can participation in clinical trials be successfully extended H into chronic disease care settings? • ow can clinical trials be organized to maximize practitioner H participation? • What are successful methods of achieving public engagement? • ow have systems, hospitals, and medical groups that are engaged H in research developed the necessary workforce competencies?

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151 APPENDIX D Summary The United States faces a pressing need for a revitalized clinical trials infrastructure. But rather than attempting to optimize clinical trials con - duct independently of health care delivery, we recommend that clinical trials and clinical care be integrated into the learning health system. The rapid evolution of integrated health systems provides a natural vehicle for accomplishing this goal, using electronic health records aggregated at the health system level and beyond. The one major exception to this approach should be for intensive biological research that we envision as taking place within a system of Innovator’s Labs connected by sophisti - cated informatics and strategic technology investments. The continuation of standardized control trials in the Traditional Labs and the develop - ment of Health Care Delivery Labs embedded within integrated health systems will provide a major improvement in the quantity, quality, and generalizability of clinical trial results (see Figure 2). Community Engage- ment Labs will need to be expanded to conduct critical trials outside tradi- tional health care delivery systems. Intense efforts will be needed in order to understand the requirements for an effective national system capable of interdigitating with developing global systems, including efforts focused on workforce development, economic analysis, and concrete operational plans. The vision described in this paper for the future of clinical research will require improved alignment among patients, payers, and pro- viders with respect to the implications of research and the choices of each stakeholder regarding receiving, funding, or providing specific ser- vices. Assuming that such alignment among stakeholders can be attained, the financial incentives to improve care, avoid waste, redundancy, and unnecessary services could result in better health outcomes, moderation of cost increases, and the opportunity for a jointly financed research and development engine to provide for continuous measurement, innovation, and improvement across the health care continuum. Given the fragmented nature of the American payer and provider landscape, a national “clini - cal research tax” applied to health care premiums could be a potential source of the funds needed to fuel the research and development engine envisioned in the integrated health care and clinical trials enterprise of the future. Some of the savings enabled by continuous quality improvement in health care could also lower the costs of care and premiums paid by patients, or at the least moderate their continued increase. The authors developed this paper in the context of the IOM Forum on Drug Discovery, Development, and Translation’s 2-year effort to assess the current status of the clinical trials enterprise and to put forward a plan to assure a robust and optimal future for clinical research. The con- sequences of the problems in the extant system are clear and the need to

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152 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE address them is urgent. There is a compelling opportunity to effectively address the gap between the research enterprise and the delivery system in the near future. We suggest attention to the development of a national agent that will bring the stakeholders together and catalyze the essential realignment of organizational mission and system-wide incentives. REFERENCES Behrman R. E., Benner J. S., Brown J. S., McClellan M., Woodcock J., and R. Platt. 2011. Developing the Sentinel System—a national resource for evidence development. N Engl J Med 10;364(6):498-499. Bennet C. L., Silver S. M., Djulbegovic B., et al. 2008. Venous thromboembolism and mortal - ity associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299:914-924. Bollyky T. J. 2011. Safer, Faster, Cheaper: Improving Clinical Trials and Regulatory Pathways to Fight Neglected Diseases: Report of the Center for Global Development Working Group on Clinical Trials and Regulatory Pathways. Washington, DC: Center for Global Develop- ment. http://www.cgdev.org/files/1425588_file_Bollyky_Clinical_Trials_FINAL.pdf (accessed April 11, 2012). Califf R. M. 2009. Clinical research sites—the underappreciated component of the clinical research system. JAMA 302(18):2025-2027. Califf R. M. and R. A. Harrington. 2011. American industry and the U.S. cardiovascular clinical research enterprise: An appropriate analogy? J Am Coll Cardiol 58(7):677-680. Califf R. M., Zarin D. A., Kramer J. M., Sherman R. E., Aberle L. H., and A. Tasneem. The clinical trials enterprise in the United States as revealed by the development of ClinicalTrials.gov as an integrated database. (In review). Canadian Institutes of Health Research. 2011. Annual Report 2010-2011. http://www.cihr-irsc. gc.ca/e/44144.html (accessed October 18, 2011). Clinical and Translational Science Awards (CTSAs). 2011. http://www.ctsaweb.org/index. cfm?fuseaction=home.aboutHome (accessed September 27, 2011). Collins F. S. 2011. The NIH National Center for Advancing Translational Sciences: How Will It Work? https://www.dtmi.duke.edu/website-administration/files/Collins%20NCATS% 20slides.pdf (accessed September 27, 2011). Coronary Drug Project Research Group. 1973. The Coronary Drug Project: Design, methods, and baseline results. Circulation 47(Suppl 1):11-179. DeVol R. C., Bedroussian A., and B. Yeo. 2011. The global biomedical industry: Preserving U.S. leadership. The Milken Institute. http://www.milkeninstitute.org/publications/ publications.taf?function=detail&ID=38801285&cat=resrep (accessed October 18, 2011). Dzau V. J., Ackerly D. C., Sutton-Wallace P., Merson M. H., Williams R. S., Krishnan K. R., Taber R. C., and R. M. Califf. 2010. The role of academic health science systems in the transformation of medicine. Lancet 375(9718):949-953. Eisenstein E. L., Collins R., Cracknell B. S., et al. 2008. Sensible approaches for reducing clinical trial costs. Clin Trials 5(1):75-84. FasterCures. 2005. Think Research: Using Electronic Medical Records to Bridge Patient Care and Research. White Paper. http://www.fastercures.org/objects/pdfs/white_papers/ emr_whitepaper.pdf (accessed October 17, 2011). FDA (Food and Drug Administration). 2006. Promoting Safe and Effective Drugs for 100 Years. http://www.fda.gov/AboutFDA/WhatWeDo/History/CentennialofFDA/ CentennialEditionof FDAConsumer/ucm093787.htm (accessed September 28, 2011).

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155 APPENDIX D TABLE 1 Characteristics of the Clinical Trials Enterprise, as Seen in the ClinicalTrials.gov Registry All Interventional Interventional All Studies Trials Trials, 2007-2010 Primary purpose, n/N (%) Treatment 59,200/75,778 59,200/75,198 28,605/38,199 (78.1) (78.7) (74.9) Prevention 8,092/75,778 8,092/75,198 4,152/38,199 (10.7) (10.8) (10.9) Diagnostic 2,655/75,778 2,655/75,198 1,489/38,199 (3.5) (3.5) (3.9) Supportive care 1,847/75,778 1,847/75,198 1,290/38,199 (2.4) (2.5) (3.4) Screening 866/75,778 286/75,198 195/38,199 (1.1) (0.4) (0.5) Health services research 900/75,778 900/75,198 733/38,199 (1.2) (1.2) (1.9) Basic science 1,882/75,778 1,882/75,198 1,735/38,199 (2.5) (2.5) (4.5) Educational/counseling/ 336/75,778 336/75,198 — training (0.4) (0.4) Primary purpose missing 20,568/96,346 4,215/79,413 2,771/40,970 (21.3) (5.3) (6.8) Type of intervention, n/N (%) Drug 53,441/84,614 52,162/79,410 24,751/40,970 (63.2) (65.7) (60.4) Procedural 10,911/84,614 9,635/79,410 4,104/40,970 (12.9) (12.1) (10.0) Biological 6,841/84,614 6,657/79,410 2,948/40,970 (8.1) (8.4) (7.2) Behavioral 7,134/84,614 6,582/79,410 3,307/40,970 (8.4) (8.3) (8.1) Device 6,662/84,614 6,012/79,410 3,799/40,970 (7.9) (7.6) (9.3) Radiation 2,361/84,614 2,292/79,410 928/40,970 (2.8) (2.9) (2.3) Dietary supplement 2,067/84,614 2,036/79,410 1,603/40,970 (2.4) (2.6) (3.9) Genetic 1,096/84,614 712/79,410 381/40,970 (1.3) (0.9) (0.9) Other 8,211/84,614 6,625/79,410 5,110/40,970 (9.7) (8.3) (12.5) continued

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156 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE TABLE 1 Continued All Interventional Interventional All Studies Trials Trials, 2007-2010 Enrollment type, n/N (%) Actual, n/N (%) 24,317/75,420 21,282/62,479 11,747/40,214 (32.2) (34.1) (29.2) 1-100 13,803/24,111 12,341/21,127 7,566/11,671 (57.2) (58.4) (64.8) 101-1,000 8,844/24,111 7,767/21,127 3,744/11,671 (36.7) (36.8) (32.1) 1,001-5,000 1,220/24,111 883/21,127 316/11,671 (5.1) (4.2) (2.7) >5,000 244/24,111 136/21,127 45/11,671 (1.0) (0.6) (0.4) Anticipated, n/N (%) 51,103/75,420 41,197/62,479 28,467/40,214 (67.8) (65.9) (70.8) 1-100 29,510/51,066 25,405/41,177 17,726/28,458 (57.8) (61.7) (62.3) 101-1,000 18,252/51,066 13,997/41,177 9,629/28,458 (35.7) (34.0) (33.8) 1,001-5,000 2,536/51,066 1,467/41,177 916/28,458 (5.0) (3.6) (3.2) >5,000 768/51,066 308/41,177 187/28,458 (1.5) (0.7) (0.7) Missing enrollment type 20,926/96,346 16,934/79,413 756/40,970 (21.7) (21.3) (1.8) Lead sponsor classification, n/N (%) Industry 31,173/93,436 28,264/79,413 15,248/40,970 (32.4) (35.6) (37.2) NIH 9,215/93,436 5,878/79,413 1,106/40,970 (9.6) (7.4) (2.7) U.S. federal (non-NIH) 1,715/93,436 1,473/79,413 547/40,970 (1.8) (1.9) (1.3) Other 54,243/93,436 43,798/79,413 24,069/40,970 (56.3) (55.2) (58.7) SOURCE: Data extracted from the database for Aggregate Analysis of ClinicalTrials.gov (AACT): https://www.trialstransformation.org/projects/improving-the-public-interface- for-use-of-aggregate-data-in-ClinicalTrials.gov/aact-database-for-aggregate-analysis-of- ClinicalTrials.gov.

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157 APPENDIX D 1000 Facts per Decision Proteomics and Other Effector Molecules 100 Functional Genetics: Gene Expression Profiles 10 Structural Genetics: e.g., SNPs, Haplotypes Human Cognitive 5 Capacity Decisions by Clinical Phenotype 1990 2000 2010 2020 FIGURE 1 Schematic depicting the increase in number of facts per clinical decision with new sources of biological data—that is, the increasing complexity of medical decision making that accompanies biomedical advances. NOTE: SNP, single-nucleotide polymorphism. R02159 SOURCE: Stead, W. W. 2010. Recalibrating Informatic’s “True North.” Speaker presen- Figure D-1 tation at AMIA Now! 2010, May 27, Phoenix, AZ. http://informatics.mc.vanderbilt. edu/sites/informatics. mc.vanderbilt.edu/files/Stead-AMIA2010-Presentation.pdf duplicated from new S-3.eps in job R01152 (accessed January 6, 2012). Reprinted with permission from William W. Stead.

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158 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE Current State The Community Innovator Tradi onal Health Care The Rest of Lab Lab Delivery Lab Health Care Transla on of New Basic Transla on from Clinical Science and Improved Knowledge into Clinical Biomedical Basic Science to Knowledge Health Prac ce and Health Research Human Studies Decision Making EARLY LATE Clinical Research Con nuum Matura on of Research in Integrated Health Systems and The Community Connected Community Sites Innovator Tradi onal Health Care The Rest of Lab Lab Delivery Lab Health Care Transla on of New Basic Transla on from Clinical Science and Improved Knowledge into Clinical Biomedical Basic Science to Knowledge Health Prac ce and Health Research Human Studies Decision Making EARLY LATE Clinical Research Con nuum FIGURE 2 This figure depicts the current segmentation of clinical trials enterprise in the United States (top graphic) contrasted with the authors’ vision of the poten - tial future organization of clinical trials (bottom graphic) built around the matura- tion of research in integrated health systems (IHSs) and community sites. Arrows below each figure depict the clinical research continuum from basic research to R02159 Figure D-2 vector, editable color

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159 APPENDIX D improved health. Blue circles indicate IHS-connected community research labs (the fourth type of lab described in this paper). These labs grow in size but stay small in number through mergers and acquisitions in the health system sector. At the same time, community engagement labs not affiliated with an IHS, shown in brown, would be connected to core traditional labs shown in green. These com - munity labs would become larger and more common. Some are all-encompassing, such as the entire city of Rochester, New York. SOURCE: Adapted from: Sung, N. S. et al. 2003. Central challenges facing the national clinical research enterprise. JAMA 289:1278-1287.

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