Topic ChaptersClinical research is vital to the well-being of our society. Defined as “research that directly involves a particular person or group of people, or that uses materials from humans, such as their behavior or samples of their tissue,” clinical research provides the scientific evidence that helps us decide which approaches to preventing, diagnosing, treating, and managing diseases are safe and effective [1].

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For much of modern medical history, many have believed that routine patient care should be kept apart from clinical research. As a result, we now have a system in which research data are collected using stand-alone systems. These systems are designed to ensure that the information gathered during research activities is valid and complete. However, having separate systems for research and care comes at a significant cost. There is growing concern that the results obtained from clinical research may not apply to “real-world” situations [2], because the research is often done under artificial conditions with volunteers who may not reflect the patients who actually suffer from a given disease or condition. What’s more, this “standalone” system requires enormous amounts of money and effort to sustain.

Finding a Better Way to Gather Medical Evidence

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For years, researchers have dreamed of a better approach to clinical research [3]. If the vast amounts of data collected during patient care could also be used as the “raw material” for clinical research, such an approach might yield findings that better reflect “real world” healthcare. It could also dramatically reduce costs and improve efficiency, as data from both care and research can be used and re-used for different purposes. Ultimately, the research and patient care communities would be able to learn together at a much faster rate. A key part of this revolution in research hinges on the widespread use of electronic health records (EHRs) that allow information to be shared among caregivers and researchers while at the same time ensuring data quality and privacy.

Although this new approach would affect the entire spectrum of research from epidemiology to clinical trials, the latter may present the most difficulties. Clinical trials provide critical evidence for guiding decisions about health and medical care. Currently, these trials are marked by an intense focus on the quality of each data item gathered during the trial. But because this focus is very expensive, it places a sharp limit on the number of trials that can be done.

Recent studies show that clinical practice guidelines used to guide therapeutic decisions often lack high-quality evidence to support key recommendations [4]. Put simply, people are harmed every day because we have not done the trials that would clearly distinguish which therapies among the many available choices should be used for a given patient. But at the same time, improvements in our understanding of biological and organizational factors that affect health outcomes are making possible a dramatic increase in the rate at which we can produce solid evidence about the balance of risks and benefits associated with health, healthcare, and the use of medical products.

If we are to hasten the development of high-quality medical evidence, we must first understand that current approaches will not meet an ever-growing demand. Clinical trials are too expensive. Of those that are done, many fail to meet their patient enrollment goals. Others suffer from other design flaws that limit the conclusions we can draw from them. The reasons driving these costs and inefficiencies are complex, and include unintended consequences of the rapid growth of well-meaning regulations [5]. Also, because most of the costs of clinical trials are related to personnel, the increasing amount of work required to achieve a given result, as well as the increasing salaries of the professionals who do this work, are pricing our current clinical trials system out of the market [6]. This has led to a growing reluctance on the part of government to engage in major trials that could change health policy, and on the part of industry to pursue development of promising new treatments.

At the same time, the widespread use of EHR and advances in information technology and informatics are creating opportunities to combine very large, complex sets of data (“big data”) in ways that until now were almost unimaginable. As systems for managing data continue to improve within U.S. health systems, the quality of electronic data is likewise improving rapidly.

The NIH Health Care Systems Research Collaboratory

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Faced with these needs and opportunities, the National Institutes of Health (NIH) initiated the NIH Health Care Systems Research Collaboratory as a Common Fund project. Common Fund projects address major issues that exceed the reach of any single NIH Institute. By design, they are high-risk undertakings with a “sunset” period of 5 to 7 years. At that point, if the program has created a path toward sustainability, the effort can be merged into more traditional NIH funding structures. On the other hand, if the program’s results show that it is a poor fit for NIH structures, it can be discontinued.

The aim of the Collaboratory is to change the way clinical research is done. As a key part of its mission, it will support innovative and collaborative projects designed to ensure that healthcare providers and patients are able to make decisions about health and healthcare based on the best evidence available. The Collaboratory is a Cooperative Agreement, meaning that the NIH and external (or “extramural”) investigators work together under joint governance. In addition to a Coordinating Center, the Collaboratory includes 4 to 7 new Demonstration Projects each year, which bring together at least two integrated health systems using EHRs as tools for data collection.

Rethinking Clinical Trials: A Living Textbook of Practical Clinical Trials is one facet of this effort. Our goal in creating Rethinking Clinical Trials is to provide a living document to guide the many different people with an interest in practical (or “pragmatic”) clinical trials [7] and health systems research. We hope that this “living textbook” will be useful to a broad spectrum of users, including the public, healthcare professionals and administrators, personnel working in academic and industry-funded clinical trials, and full-time clinical trialists.

The Living Textbook’s topic sections are written, reviewed, and kept up to date by experts in their respective fields. Each topic is aligned with a Collaboratory Core or Working Group. Subtopics are organized to provide readers with both broad overviews and more detailed and granular information. This layered approach will allow interested readers to drill down to highly detailed operating procedures for practical clinical trials. Readers will also be able to access links for definitions and other resources. In addition, in cases where other groups have already created excellent resources, we have linked to them through our Collaboratory Knowledge Repository, which serves as an archive for news, official Collaboratory documents and products, and approved external materials.

Given the rapid pace of change in the field of practical clinical trials, we expect that significant parts of this electronic textbook will be added to, refreshed, and perhaps even rewritten over the next 5 years. However, throughout this change, we will continue to highlight elements that reflect an expert consensus regarding standard approaches and best practices in the design and conduct of practical clinical trials.


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1. National Institute of Child Health and Human Development website. Clinical trials and clinical research. Available at Accessed June 10, 2013.

2. Ioannidis JP. Why most published research findings are false. PLoS Med. 2005;2:e124. PMID: 16060722. doi:10.1371/journal.pmed.0020124.

3. Rosati RA, McNeer JF, Starmer CF, Mittler BS, Morris JJ Jr, Wallace AG. A new information system for medical practice. Arch Intern Med. 1975;135:1017-24. PMID: 1156062. doi:10.1001/archinte.1975.00330080019003.

4. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA. 2009;301(8):831-41. PMID:19244190. doi: 10.1001/jama.2009.205.

5. Kramer JM, Smith PB, Califf RM. Impediments to clinical research in the United States. Clin Pharmacol Ther. 2012;91:535-41. PMID: 22318614. doi: 10.1038/clpt.2011.341.

6. Califf RM, Harrington RA. American industry and the U.S. Cardiovascular Clinical Research Enterprise an appropriate analogy? J Am Coll Cardiol. 2011;58:677-80. PMID: 21816302. doi: 10.1016/j.jacc.2011.03.048.

7. Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA. 2003;290:1624-32. PMID: 14506122. doi:10.1001/jama.290.12.1624.

Topic chapter originally published on November 1, 2013.

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Introduction: Introduction. In: Rethinking Clinical Trials: A Living Textbook of Pragmatic Clinical Trials. Bethesda, MD: NIH Health Care Systems Research Collaboratory. Available at: Updated May 21, 2019.