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Introduction

Efficiently generating medical evidence and translating it into practice implies a “learning health care system” in which the divide between clinical practice and research is diminished and ultimately eliminated. Such a system relies on efficiently generating timely, accurate evidence to deliver on its promise of diminishing the divide between clinical practice and research. There are growing indications, however, that the current health care system and the clinical research that guides medical decisions in the United States falls far short of this vision. The process of generating medical evidence through clinical trials in the United States is expensive and lengthy, includes a number of regulatory hurdles, and is based on a limited infrastructure. The link between clinical research and medical progress is also frequently misunderstood or unsupported by both patients and providers.

Generating relevant medical evidence is an ongoing process subject to the dynamic nature of health care. The focus of clinical research changes as diseases emerge and new treatments create cures for old conditions. As diseases evolve, the ultimate goal remains to speed new and improved medical treatments to patients throughout the world. To keep pace with rapidly changing health care demands, clinical research resources need to be organized and on hand to address the numerous health care questions that continually emerge. Improving the overall capacity of the clinical research enterprise will depend on ensuring that there is an adequate infrastructure in place to support the investigators who conduct research, the patients with real diseases who volunteer to participate in experimental research, and the institutions that organize and carry out the trials.



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1 Introduction E fficiently generating medical evidence and translating it into practice implies a “learning health care system” in which the divide between clinical practice and research is diminished and ultimately eliminated. Such a system relies on efficiently generating timely, accurate evidence to de- liver on its promise of diminishing the divide between clinical practice and research. There are growing indications, however, that the current health care system and the clinical research that guides medical decisions in the United States falls far short of this vision. The process of generating medical evidence through clinical trials in the United States is expensive and lengthy, includes a number of regulatory hurdles, and is based on a limited infra- structure. The link between clinical research and medical progress is also frequently misunderstood or unsupported by both patients and providers. Generating relevant medical evidence is an ongoing process subject to the dynamic nature of health care. The focus of clinical research changes as diseases emerge and new treatments create cures for old conditions. As diseases evolve, the ultimate goal remains to speed new and improved medical treatments to patients throughout the world. To keep pace with rapidly changing health care demands, clinical research resources need to be organized and on hand to address the numerous health care questions that continually emerge. Improving the overall capacity of the clinical research enterprise will depend on ensuring that there is an adequate infrastructure in place to support the investigators who conduct research, the patients with real diseases who volunteer to participate in experimental research, and the institutions that organize and carry out the trials. 1

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2 TRANSFORMINg ClINICAl RESEARCh IN ThE UNITEd STATES To address these issues and better understand the current state of clinical research in the United States, the Institute of Medicine’s (IOM’s) Forum on Drug Discovery, Development, and Translation (the “Drug Fo- rum”) held a 2-day workshop on October 7−8, 2009, titled Transforming Clinical Research in the United States. This workshop laid the foundation for a broader initiative of the Forum addressing different aspects of clini- cal research. Future Forum plans include the following: further examining regulatory, administrative, and structural barriers to the effective conduct of clinical research; developing a vision for a stable, continuously funded clinical research infrastructure in the United States; and considering strate- gies and collaborative activities to facilitate more robust public engagement in the clinical research enterprise. This report builds on a body of related IOM work. Focused on the national objective of achieving the best health outcome for each patient, the IOM Roundtable on Value & Science-Driven Health Care explores the need for a learning health care system in the United States and possible ways such a system can create value in health care interactions. Reports based on the Roundtable’s recent workshops include The Healthcare Imperative: Lowering Costs and Improving Outcomes (IOM, 2009a) and Value in Health Care: Accounting for Cost, Quality, Safety, Outcomes, and Innova- tion (IOM, 2010). The IOM’s National Cancer Policy Forum is discussing strategies for improving cancer clinical trials and the National Cancer Institute’s (NCI’s) Cooperative Group program. That Forum’s recent re- ports include Multi-Center Phase III Clinical Trials and NCI Cooperatie groups (IOM, 2009b) and Improing the Quality of Cancer Clinical Trials (IOM, 2008). THE CLINICAL TRIALS PROCESS The focus of the workshop was clinical trials—a type of clinical re- search that prospectively evaluates the risks and benefits of a drug, device, behavioral intervention, or other form of treatment. The materials and resources (human capital, financial support, patient participants, and in- stitutional commitment) available to conduct such research can vary by research sponsor, disease area being studied, and type of research question being asked. Once a research question has been posed and the concept for a study has been defined, funding must be secured to continue the process. The study protocol, which is an extensive blueprint for the trial and how it will be conducted, is also required to be submitted to the relevant institu- tions and organizations that provide ethical and regulatory approval. All clinical trials are designed to answer one or more specific ques- tions. They can vary by the study population chosen (number of subjects, as well as criteria to enter the study) and the type of question(s) posed. For

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 INTROdUCTION example, clinical trials to gain U.S. Food and Drug Administration (FDA) approval for a new drug are designed to show its safety and efficacy over the course of a few years. These trials seek to answer narrowly defined ques- tions related to safety and efficacy in a carefully selected group of study par- ticipants most likely to experience the intended effects of the drug. Clinical trials conducted without the goal of regulatory approval (e.g., government sponsored) might test a drug or intervention in a diverse group of study participants, include a long time frame for follow-up of study subjects, and address a broader set of questions. The workshop examined a variety of clinical trials, including those sponsored by industry and government, but the focus was on large, multicenter trials. The clinical trials process for gaining regulatory approval of a new drug has traditionally been described in five discrete phases. Each phase seeks to answer a different set of questions. An increasing number of volunteers are included in each phase as the trial progresses and attempts to build a case that an experimental drug or treatment is safe and effective against the disease or condition it is intended to treat. Phase 0 trials are exploratory, first-in-human studies designed to de- termine whether a drug affects the human body as expected from earlier preclinical, animal studies. These trials involve a small number of people (10−15) who receive a low, nontherapeutic dose of the investigational drug. These preliminary trials help companies rank a number of different drug candidates in their pipeline and make decisions about which candidates should be developed. Phase I clinical trials test an experimental drug or treatment for the first time in a small group of people (20−80) over the course of a few weeks or a month. Their goals are to assess the safety of the drug or treatment, find a safe dosage range, and identify any side effects. In phase II trials, a larger group of people (100−300) receives the ex- perimental drug to determine whether it is effective and further evaluate its safety. These trials involve subjects with the target disease and usually last months. Once preliminary evidence from phase II reveals that a treatment is ef- fective, phase III trials are designed to fully examine the risk/benefit profile of an experimental drug or treatment and test it over a longer period of time in a broader population (1,000−3,000). Because these trials are the last phase in the preapproval process, they are often referred to as “pivotal” trials. Phase IV, or post-marketing, trials take place after a drug has been ap- proved. They provide additional evidence on the risks and benefits of the drug or treatment and how it can be used optimally. As a new drug progresses through the development pipeline, costs rise with each phase. Phase III clinical trials have become extraordinarily expen-

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 TRANSFORMINg ClINICAl RESEARCh IN ThE UNITEd STATES sive. One study found that on average, drug development costs for an ap- proved compound were $15.2 million in phase I, $41.7 million in phase II, and $115.2 million in phase III (Di Masi et al., 2003, p. 171). As reported in Chapter 3, a large, global clinical trial involving 14,000 patients and 300 research sites can cost approximately $300 million. Also contributing to the already high-risk and high-cost drug development process, patient enroll- ment and physician participation in clinical trials are considered by many to be inadequate to sustain a vigorous drug development pipeline, and clinical research is increasingly shifting overseas (see Chapter 3). WORKSHOP SCOPE AND OBJECTIVES Workshop participants included clinical trial experts from academia, government, industry, and patient advocacy groups. The workshop focused primarily on large, multisite, phase III clinical trials. NIH trials that were not designed to gain regulatory approval, but address clinically important issues, were also presented. In addition, examples of post-marketing studies resulting from federal requirements were also presented during the work- shop. Presentations highlighted clinical trials in four disease areas: cardio- vascular disease (acute myocardial infarction and heart failure), depression, cancer, and diabetes. These four areas were chosen because they represent a range of diseases: acute life-threatening conditions (acute myocardial in- farction); chronic life-threatening conditions (heart failure and cancer); and chronic, not acutely life-threatening conditions (depression and diabetes). Clinical trials vary across the conditions being studied. For instance, trials in breast cancer require long-term patient follow-up to capture outcomes that are 5 to 15 years into the future. Conversely, trials treating acute myocardial infarction (heart attack) measure short-term patient outcomes within hours, days, or weeks. For each disease being treated in a clinical trial, the patient population varies as do the methods used by investigators to locate, classify, recruit, and retain patients. Fundamental differences in clinical practice and what is viewed as appropriate exist across each of the diseases chosen as the focus of the workshop. The workshop sought to ex- amine how trials are being conducted in these four areas and draw lessons from each that can be applied more broadly. The workshop also focused primarily on the randomized controlled trial (RCT), which although labor- intensive and expensive to conduct, is the gold standard for producing high-quality evidence. The workshop had three main objectives: • to examine the state of clinical research in the United States; • o identify areas of strength and weakness in the current clinical trial t enterprise by examining trials in the above four disease areas; and