1

Introduction1

Recognition is growing that the clinical trials enterprise (CTE)2 in the United States faces substantial challenges impeding the efficient and effective conduct of clinical research to support the development of new medicines and evaluate existing therapies. A gap has been identified between the desired state where medical care in the United States is provided solely based on high-quality evidence—and the reality—where we have limited ability to generate timely and practical evidence. There have increasingly been calls for transformation of the CTE in the United States to support the efficient development of breakthrough medicines and interventions and the evidence needed for health care decision making. Leaders in research and health care convened to discuss this visionary quest at a 2-day workshop held in November 2011 by the Institute of Medicine (IOM) Forum on Drug Discovery, Development, and Translation.

The workshop focused primarily on one type of clinical investigation, randomized controlled trials (RCTs) (see Sidebar at the end of Chapter 1). RCTs are traditionally pivotal studies for drug development and are often the most costly and challenging to conduct. RCTs are studies that assess

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1The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop.

2The CTE is a broad term that encompasses the full spectrum of clinical trials and their applications. The CTE includes the processes, institutions, and individuals that eventually apply clinical trial findings to patient care. (See the glossary of key terms in Appendix K for additional definitions.)



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1 Introduction 1 Recognition is growing that the clinical trials enterprise (CTE)2 in the United States faces substantial challenges impeding the efficient and effec- tive conduct of clinical research to support the development of new medi- cines and evaluate existing therapies. A gap has been identified between the desired state where medical care in the United States is provided solely based on high-quality evidence—and the reality—where we have limited ability to generate timely and practical evidence. There have increasingly been calls for transformation of the CTE in the United States to support the efficient development of breakthrough medicines and interventions and the evidence needed for health care decision making. Leaders in research and health care convened to discuss this visionary quest at a 2-day work- shop held in November 2011 by the Institute of Medicine (IOM) Forum on Drug Discovery, Development, and Translation. The workshop focused primarily on one type of clinical investigation, randomized controlled trials (RCTs) (see Sidebar at the end of Chapter 1). RCTs are traditionally pivotal studies for drug development and are often the most costly and challenging to conduct. RCTs are studies that assess 1 The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. 2 The CTE is a broad term that encompasses the full spectrum of clinical trials and their applications. The CTE includes the processes, institutions, and individuals that eventually apply clinical trial findings to patient care. (See the glossary of key terms in Appendix K for additional definitions.) 1

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2 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE both the risks and the benefits (usually the efficacy, or performance under ideal conditions) of a drug or other clinical intervention. A core premise of the workshop was that RCTs serve as the foundation of the CTE. In RCTs, responses by a group of trial participants randomly assigned to receive a drug or other intervention are compared with the progress of a similar group of trial participants who instead randomly receive the assignment of placebo or alternative treatment. To accomplish this comparison of therapeutic effects, trial participants and staff must have no input into whether they are assigned to the experimental or control group or knowl- edge about their assignment until after the trial is ended, except under extraordinary circumstances. The Food and Drug Administration (FDA) has traditionally required drug development firms to use RCTs to obtain new drug approvals. Workshop participants also discussed other types of investigations (such as nonrandomized trials, observational studies, and clinical effectiveness research), which, like RCTs, examine the relative success of specific drugs or other interventions and provide additional opportunities to better understand existing therapies. In the United States, clinical trials are conducted, funded, and regu- lated by several important components of the health care sector. Box 1-1 identifies some of these stakeholders. BOX 1-1a Stakeholders in the U.S. Clinical Trials Enterprise Clinical Trial Sponsors • Federal agencies: National Institutes of Health (NIH) Agency for Healthcare Research and Quality (AHRQ) U.S. Department of Defense (DoD) U.S. Centers for Disease Control and Prevention (CDC) Department of Veterans Affairs (VA) • Nongovernmental organizations that fund and/or conduct clinical trials: Academic institutions Patient advocacy groups (e.g., Cystic Fibrosis Foundation) Philanthropic foundations (e.g., The Bill & Melinda Gates Foundation) • Industry (pharmaceutical, biotechnology, and medical device companies) Clinical Trial Regulators • ederal agencies (e.g., FDA, Centers for Medicare & Medicaid Services [CMS]) F • Institutional review boards (IRBs) • nternational regulatory agencies and country-specific regulatory authorities for I multicenter clinical trials outside the United States

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3 INTRODUCTION BOX 1-1 Continued Clinical Trial Participants • Organizations Academic health science systems (AHSSs)b Community-based clinical practices Public and private hospitals Public health departments Contract research organizations (CROs) Government laboratories Industry Private research institutes Clinical research networks (e.g., Children’s Oncology Group) • linical investigators and research teams at clinical trial sites (see Chapter 3 C for a detailed discussion of the clinical trials workforce) • tudy participants (patients and healthy volunteers who decide to participate S in a clinical trial) Primary Consumers of Clinical Trial Results • cientists and researchers S • ealth care delivery system H • ealth care purchasers and payers (e.g., Medicare, Blue Cross and Blue Shield, H individual patients) • ndustry I • atient and disease advocacy organizations P • ndividual patients and families I Beneficiaries of Clinical Trial Results • ociety S • ndividual patients and families I a The description of the CTE in this box is based on workshop planning committee dis- cussions and Sung et al., 2003, Central Challenges Facing the National Clinical Research Enterprise, JAMA 289:1278-1287. b For more information on the development of AHSSs, see Dzau et al., 2010, The Role of Academic Health Science Systems in the Transformation of Medicine, Lancet 375:949-953. Taken as a whole, these interconnected stakeholders and their activi - ties constitute the CTE. In addition to supporting the development of drugs, biologicals, and medical devices, the CTE informs quality improve- ment in health care and clinical decision making. The CTE is the arena where new interventions are tested under “laboratory conditions,” and where existing interventions can be further evaluated for effectiveness under the standard conditions of patient care.

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4 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE DEFINING THE PROBLEM Box 1-2 outlines some of the challenges that currently jeopardize the viability and strength of the CTE in the United States. Many of these challenges have been considered previously. For instance, the challenge of patient enrollment and retention in clinical tri - als is addressed in a recent summary of a Forum workshop held earlier in 2011 (IOM, 2012a). That summary describes numerous difficulties in public engagement in clinical trials, including the need for more robust information sharing among researchers, patients, and physicians about RCT opportunities; the availability of experimental treatments outside of participating in an RCT; inadequate funding mechanisms to support RCT participation; lack of prestige allocated within the medical school setting to the conduct of clinical trials; and delays and logistical problems associated with a fragmented clinical trials infrastructure3 and health care system. The summary (IOM, 2012a) further describes possible ways to overcome these difficulties. Chapter 3 of the present report describes difficulties in engaging patients, the public, and physicians in clinical research in additional detail. Owing to these and other difficulties, including those enumerated in Box 1-2, new RCT study designs are being developed to increase the efficiencies of trial design and the applicability of clinical trial results. Promising innovations include adaptive designs in which a prespecified plan defines prescribed changes to study end points and other criteria over the course of a study based on collected data and the treatment responses of prior participants; pragmatic trials that investigate an inter- vention’s effectiveness in real-world conditions, rather than efficacy only (this approach may involve fewer inclusion and exclusion criteria for individuals to participate in the trial, as well as longer study timelines that seek to evaluate patient-centered outcome measures or end points); and virtual or web-based clinical trials that involve the online registration of study participants to overcome enrollment challenges posed by the cur- rent geographic distribution of clinical trial sites (IOM, 2012a). A number of workshop participants expressed the belief that adoption of these trial designs and other innovations will help to fortify the CTE. 3 The clinical trials infrastructure, part of the broader clinical research enterprise, refers to the necessary resources (human capital, financial support, patient participants, information systems, regulatory pathways, and institutional commitment) and the manner in which they are organized and brought together to conduct a clinical trial. The clinical trials infrastruc - ture is currently developed on a trial-by-trial basis, or in a sponsor-specific manner, resulting in “one-off” trials that bring together substantial resources that are subsequently disbanded. In previous and ongoing Forum discussions, many participants in Forum activities have suggested that efforts to develop a consistent and reliable clinical trials infrastructure that lived beyond the single trial could increase the efficiency and effectiveness of the entire CTE.

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5 INTRODUCTION BOX 1-2a Selected Challenges Facing the U.S. Clinical Trials Enterprise • ncreasingly high costs, lengthy delays, and inconsistencies associated with elab- I orate administrative procedures established by risk-averse research organizations • oncern over lack of proportionality, clarity, or consistency in regulatory re- C quirements and compliance protocols • rowing competition from other countries, where research costs are lower or G governments are supporting growth in their indigenous medical research industry • ecline in the number of medical researchers, coupled with the lack of stable D funding and employment • ow rates of enrollment and retention of people in clinical trials, coupled with L lackluster recruitment efforts by physicians and other providers of care, so that many planned trials are not completed • igidity of the research questions that are asked, and exclusion from studies of R many types of patients who might eventually benefit from the treatment (so that results of trials often are not applicable or generalizable to the typical patient population) • ocietal or individual biases toward providing potentially promising treatments S to all individuals who might benefit from them, as opposed to randomizing individuals to receive or not receive the treatment in an RCT • nconsistent adoption of clinical trial results by health care providers, payers, I and patients in making decisions regarding individual patient care a This box provides a nonexhaustive list of some of the challenges to the CTE noted in the Discussion Papers contained in Appendixes D-G and suggested by individual workshop participants. LINKING THE TRANSFORMATION OF THE CLINICAL TRIALS ENTERPRISE AND IMPROVING QUALITY OF CARE The scientific process is actually part of the very basic fiber of what we do as clinicians in seeing a patient. . . . [W]hen we ask a patient what is wrong with . . . [them], we are actually identifying the problem, and when we come up with a working diagnosis, that in fact is a hypothesis, and . . . we do our physical examination and our laboratory tests as our experiment. —Rebecca D. Jackson, The Ohio State University Efforts to transform the U.S. CTE exist within a broader goal to develop a health care system with dramatically improved quality of care. In this improved health care system, clinicians, together with patients,

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6 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE families, and health professions colleagues, could formulate individual treatment plans based on interventions that have achieved the greatest degree of success with similar patients across the country and based on evidence available to support these decisions. In turn, the current patient’s experiences with the chosen treatment would be added back to the body of evidence, effectively creating a learning health system that constantly builds on its experiences for the benefit of future patients. A transition to evidence-based health care has been years in the mak- ing. For example, beginning in 2009 with its first workshop in the present series on clinical trials, the Forum has explored ways to overcome chal- lenges in conducting clinical trials in specific disease areas, as well as in the broader population. The summary report on that workshop began: “Efficiently generating medical evidence and translating it into prac - tice implies a ‘learning health care system’ in which the divide between clinical practice and research is diminished and ultimately eliminated” (IOM, 2010a). In this way, the goal of transforming the CTE exists within a broader context of clinical research and the development of a learning health system. Several IOM efforts have either emphasized (such as IOM, 2011a) or are now investigating the importance and features of a learn- ing health system, that is, a system in which “knowledge generation is so embedded into the core of the practice of medicine that it is a natural outgrowth and product of the health care delivery process and leads to continual improvement in care.”4 The CTE is broadly recognized as a key aspect of a learning health system. Features of a learning health system are also likely to include a focus on comparative effectiveness research (CER), to help patients and clinicians choose a treatment approach that is likely to work best for the specific patient; this research frontier, too, has been the subject of a continuing succession of IOM reports (IOM, 2009, 2011b). As was simply stated by one such report, “Patients should receive care based on the best avail - able scientific evidence. Care should not vary illogically from clinician to clinician or from place to place” (IOM, 2001). Learning health system features also are likely to include use of electronic health records (EHRs) to accumulate data about the results of specific treatments across different types of patients. Well-built electronic records would enable health pro - fessionals to enter data about treatments into the patient record routinely. Systems technologists could then assemble treatment-specific files across all patients while purging the files of patient identifiers, and researchers could in turn mine these files to determine which treatments have worked 4 This definition of a learning health system (formerly, “learning healthcare system”) was developed by the IOM Roundtable on Evidence-Based Medicine (now called the Roundtable on Value and Science–Driven Health Care) (IOM, 2007).

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7 INTRODUCTION best for which types of patients. Several workshop participants noted, however, that while use of EHRs in a learning health system would greatly enhance the timely generation of medical evidence, use of EHRs will not replace the need for well-designed RCTs. Interest in harnessing scientific evidence for improved medical decision making and the benefit of patients has also emerged in sev - eral federal government venues. The NIH has provided leadership in the national campaign to enrich health care decisions with scientific evidence. The seminal NIH Roadmap for Medical Research, released in 2003, envisioned a nationwide system in which EHRs would be uni - versally used to gather evidence about the results of specific treatments obtained for nearly all patients who undergo them. That roadmap has led the NIH Common Fund to support high-risk research, inter- disciplinary research, and public–private partnerships (NIH, Division of Program Coordination, Planning and Strategic Initiatives, 2011). A recent presidential commission likewise advocated using EHRs to build data sets on treatment results, thereby facilitating clinical trials and other medical research—a use of health information technology (IT) that goes beyond merely supporting individual clinical decisions (Executive Office of the President, 2010). One Department of Health and Human Services (HHS) agency in particular, the AHRQ, has as its mission the improvement of the “quality, safety, efficiency, and effec - tiveness of health care for all Americans . . . [and] supports research that helps people make more informed decisions and improves the quality of health care services” (AHRQ, 2011). Despite efforts to forge a stronger relationship between the scientific development of medical evidence and clinical practice, much remains to be done. For example, fewer than 15 percent of the major recommendations contained in the clinical practice guidelines for infectious disease (Lee and Vielemeyer, 2011) and cardiovascular disease (Tricoci et al., 2009) are based on high- quality evidence. PURPOSE AND STRUCTURE OF THE WORKSHOP This Forum workshop brought together diverse stakeholders in the CTE. Held in Washington, DC, the workshop was titled “Envisioning a Transformed Clinical Trials Enterprise in the United States: Establishing an Agenda for 2020.” The meeting was intended to frame the problem of how to transform the CTE and to discuss a vision that would make it efficient, effective, and fully integrated into the health care system of 2020. Box 1-3 lists the workshop task and objectives. The workshop’s approximately 150 attendees were drawn primarily from the fields of biomedical and other medical research, regulatory science, pharmaceuti -

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8 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE BOX 1-3 Workshop Task and Objectives • rame the problem and discuss a vision for a CTE that is efficient and effective F and fully integrated into the health delivery system of 2020. • efine how the envisioned CTE differs from the current system and suggest D approaches to transform our current system into a learning system. • onsider the following core themes in framing an agenda to effect transforma- C tion of the U.S. CTE: Providing a vision for a CTE in the health care system of 2020 — Developing a robust clinical trials workforce — Aligning cultural and financial incentives — Building an infrastructure to support a transformed CTE — • orkshop presentations and panel discussions will be supported and supple- W mented by Discussion Papers prepared by participants in Forum activities. Each of the four workshop sessions are prefaced by presentations from Discus- sion Paper authors. cal research and manufacturing, health care delivery, patient advocacy, voluntary health associations, and academic medicine. In welcoming the participants, workshop chair and Forum co-chair Jeffrey Drazen, Editor-in-Chief, New England Journal of Medicine, described the Forum as a “neutral venue for academic, industry, and the public sec - tor to propose ideas for the future.” Four Discussion Papers were prepared in draft form by Forum mem- bers and participants in advance of the workshop, and they appear in a revised, finalized version in Appendixes D, E, F, and G. The draft papers served as the bases of deliberation for four corresponding plenary ses - sions of the workshop. The titles of the four plenary workshop sessions and the corresponding Discussion Papers were as follows: • Session I: “Framing the Need for Change: Envisioning a Clinical Trials Enterprise in the Health Care System of 2020”5 • Session II: “Developing a Robust Clinical Trials Workforce”6 • Session III: “Aligning Cultural and Financial Incentives”7 5 Corresponding Discussion Paper “The Clinical Trials Enterprise in the United States: A Call for Disruptive Innovation” (see Appendix D). 6 Corresponding Discussion Paper “Developing a Robust Clinical Trials Workforce” (see Appendix E). 7 Corresponding Discussion Paper “Transforming the Economics of Clinical Trials” (see Appendix F).

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9 INTRODUCTION • Session IV: “Building an Infrastructure to Support a Transformed Clinical Trials Enterprise”8 In the workshop’s final session (Session V), “Developing an Agenda for the Creation of a Transformed Clinical Trials Enterprise,” the chairs of each of the plenary sessions summarized those discussions, a panel of six presenters addressed practical ways to help achieve transformation by 2020, and the panelists and workshop participants engaged in an open discussion about specific suggestions on each of the following topics: • Suggest long-term strategic goals that can be identified and met to further transformation of the CTE. • Describe the top three priorities for reforming the CTE based on their urgency, scope, or importance to the transformation effort. • Consider opportunities that represent “low-hanging fruit” or are realistic short-term goals for improving the productivity and effec- tiveness of the U.S. CTE. • Suggest ways that disease and patient advocacy networks, volun- tary health associations, and other nonprofit organizations could contribute to, or coordinate with, efforts to build an infrastructure for clinical trials. • Describe opportunities and strategies for developing and leverag- ing a workforce to support the CTE. • Suggest the elements of an agenda essential for moving forward, by stakeholder (namely, health care delivery systems, pharmaceu - tical and biotechnology companies, payers, disease and patient advocacy networks, voluntary health associations, academic medi- cal centers and universities, and regulators and federal agencies funding research). The group discussion ended with suggestions for each of several key constituencies: researchers, the pharmaceutical and biotech industries, payers, consumer advocates, academic medical centers, and regulators. Workshop participants expressed a broad range of opinions about the likelihood of overall success of CTE transformation. But several expressed optimism and asserted that the ambitious effort must be made. Illustrat - ing this vision, Clyde Yancy, Chief of Cardiology, Northwestern Univer- sity Feinberg School of Medicine, and Associate Director, Bluhm Cardio - vascular Institute, Northwestern Memorial Hospital, said the goal is a “big solution. . . . I think if we are really talking about transforming an 8 Corresponding Discussion Paper “Developing a Clinical Trials Infrastructure” (see Appendix G).

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10 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE enterprise, it can’t be transformed with iterative steps. There has to be some significant metamorphosis that takes place.” ORGANIZATION OF THE REPORT This report summarizes the main points made at the workshop dur- ing both the formal presentations and the discussions among participants. Observations and recommendations made by individual participants at the workshop do not represent the formal positions of the IOM; however, they have provided valuable input to the Forum and to the IOM as both bodies deliberate on future initiatives. Presentations at the workshop addressed the following topics: • incorporating the CTE into community clinical practice, the sug- gested benefits of doing so, and challenges likely to arise along the way (Chapter 2); • enhancing interest in, and understanding of, the importance of clinical trials—from building the workforce to conduct trials, to engaging the nation to support and take part in trials (Chapter 3); • creating a new business model for clinical trials by incorporating technologic advances and increased efficiencies and by appropri- ately framing regulatory issues (Chapter 4); • designing and developing an infrastructure to support clinical rials t (Chapter 5); and • the major viewpoints expressed at the workshop and possible next steps suggested by individual workshop participants (Chapter 6).

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11 INTRODUCTION Sidebar: Clinical Trials and Clinical Research in the Context of This Workshop Although the focus of the workshop was on clinical trials to support drug devel- opment and evaluation, specifically RCTs, there was also significant discussion of the broader topic of clinical research (e.g., the use of observational data for CER and evaluations of the safety and quality of medical care). Clinical trials are a type of clinical research to evaluate the effects of one or more treatments or interven- tions in a group of humans—that is, the safety and efficacy of new or existing treat- ments (see glossary of terms at Appendix K). The workshop discussions reflected many participants’ view that translating scientific discoveries into medical products involves not only the clinical trials for development of new products but also the broader clinical research methods and approaches that will guide a product’s use in the clinical setting. For example, the discussion in Chapter 2 surrounding the development of a learning health system covered the role of clinical trials in clinical settings (i.e., through the use of EHRs) but also the use of observational clinical re- search methods to extract value from the large volume of clinical data obtained in health care delivery. Workshop participants discussed a wide range of research methods that could engage patients and clinicians and build upon a clinical trial’s determinations of safety and efficacy (i.e., can it work under ideal circumstances?) to evaluate clini- cal effectiveness (i.e., can it work in real world, clinical practice settings?). It was noted at the workshop that the full complement of clinical research methods will be necessary to improve our understanding of the questions that emerge through the lifecycle of a medical product. Workshop discussions included the terms clinical trials and clinical research, and this summary report uses both terms throughout as appropriate, to reflect the intention of participants speaking to the more narrow clinical trials for drug development and evaluation of existing therapies versus use of the broader term clinical research to encompass observational, non-intervention studies and other practices.

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