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Introduction and Themes of the Workshop
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Stem cells offer tremendous promise for advancing health and medicine. Whether being used to replace damaged cells and organs or else by supporting the body’s intrinsic repair mechanisms, stem cells hold the potential to treat such debilitating conditions as Parkinson’s disease, diabetes, and spinal cord injury (Scadden and Srivastava, 2012). Clinical trials of stem cell treatments are under way in countries around the world, but the evidence base to support the medical use of stem cells remains limited (Bianco, 2013; Daley, 2012) (see Box 1-1).

Despite this paucity of clinical evidence, consumer demand for treatments using stem cells has risen, driven in part by a lack of available treatment options for debilitating diseases as well as direct-to-consumer advertising and public portrayals of stem cell–based treatments. Clinics that offer stem cell therapies for a wide range of diseases and conditions have been established throughout the world, both in newly industrialized countries such as China, India, and Mexico and in developed countries such as the United States and various European nations (Lau et al., 2008). Though these therapies are often promoted as being established and effective, they generally have not received stringent regulatory oversight and have not been tested with rigorous trials designed to determine

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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. Statements, recommendations, and opinions expressed are those of individual presenters and participants, are not necessarily endorsed or verified by the Institute of Medicine or the National Academy of Sciences, and should not be construed as reflecting any group consensus.



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1 Introduction and Themes of the Workshop1 Stem cells offer tremendous promise for advancing health and medi- cine. Whether being used to replace damaged cells and organs or else by supporting the body’s intrinsic repair mechanisms, stem cells hold the potential to treat such debilitating conditions as Parkinson’s disease, dia- betes, and spinal cord injury (Scadden and Srivastava, 2012). Clinical trials of stem cell treatments are under way in countries around the world, but the evidence base to support the medical use of stem cells re- mains limited (Bianco, 2013; Daley, 2012) (see Box 1-1). Despite this paucity of clinical evidence, consumer demand for treatments using stem cells has risen, driven in part by a lack of available treatment options for debilitating diseases as well as direct-to-consumer advertising and public portrayals of stem cell–based treatments. Clinics that offer stem cell therapies for a wide range of diseases and conditions have been established throughout the world, both in newly industrialized countries such as China, India, and Mexico and in developed countries such as the United States and various European nations (Lau et al., 2008). Though these therapies are often promoted as being established and effective, they generally have not received stringent regulatory over- sight and have not been tested with rigorous trials designed to determine 1 The planning committee’s role was limited to planning the workshop, and the work- shop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, are not necessarily endorsed or veri- fied by the Institute of Medicine or the National Academy of Sciences, and should not be construed as reflecting any group consensus. 1

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2 STEM CELL THERAPIES BOX 1-1 Stem Cell Potential When a stem cell divides it gives rise to two daughter cells, one of which is at the same stage of development as the original cell, explained Irving Weissman, Virginia and D. K. Ludwig Professor for Clinical Investigation in Cancer Research at the Stanford University School of Medicine. This property of one daughter cell being at the same stage of development as the parent cell is called self-renewal, and it is unique to stem cells. In the body’s blood-forming systems—whether bone marrow, mobilized peripheral blood, or umbilical cord blood—only about 1 in 20,000 cells is appropriately called a stem cell. Beginning in 1988, Weissman and his colleagues learned how to isolate blood-forming stem cells. These cells have been observed to regenerate only blood and no other tissue, despite strenuous efforts to demonstrate otherwise, Weissman said. Only pluripotent stem cells can form cells of different tissues. To treat people using regenerative medicine, it is essential to have robust, rapid, and sustained regeneration, Weissman said. Any such regenerative-medicine treatment must have gone through four steps: • A discovery that has been independently replicated, • Preclinical and published proof of principle, • Application to a national or other body for successive trials to demonstrate safety and efficacy, and • Approval from that body that the trial was safe and efficacious. Today, almost no purified cell products in the clinic have met these four criteria, according to Weissman. their safety and likely benefits (Daley, 2012). In the absence of substan- tiated claims, the potential for harm to patients—as well as to the field of stem cell research in general—may outweigh the potential benefits (Barclay, 2009; Bianco, 2013). To explore these issues, the Institute of Medicine (IOM), the National Academy of Sciences (NAS), and the International Society for Stem Cell Research (ISSCR) held a workshop in Washington, DC, on November 18, 2013, titled Stem Cell Therapies: Opportunities for Ensuring the Quality and Safety of Unregulated Clinical Offerings. The workshop brought together researchers, clinicians, patients, policy makers, and oth- ers from North America, Europe, and Asia to examine the global pattern of treatments and products being offered, the range of patient experienc- es, and options to maximize the well-being of patients, either by protect- ing them from treatments that are dangerous or ineffective or by steering

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INTRODUCTION AND THEMES OF THE WORKSHOP 3 them toward treatments that are effective. The workshop was not intend- ed to be a fully comprehensive analysis of the practice of offering stem cell therapies and thus it does not represent activities in all countries where clinics exist. Box 1-2 lists the objectives of the workshop.2 BACKGROUND Many different kinds of stem cell treatments are being offered around the world, said Alta Charo, Warren P. Knowles Professor of Law and Bioethics at the University of Wisconsin–Madison and chair of the workshop planning committee. Some are available as procedures offered by clinics, while others, such as skin care products, are available for di- rect purchase through online marketplaces. These treatments are de- scribed as using stem cells from other humans, from animals, or from plants; feature the use of autologous stem cells, in which cells are ex- tracted from an individual, manipulated in a laboratory, and reinfused or reimplanted into that same person; or advertise the use of tissue-specific stem cells. BOX 1-2 Objectives of the Workshop Developed by the Planning Committee • Discuss the current environment in which patients are receiving un- regulated stem cell offerings. • Examine the stem cell treatments that are being offered. • Assess the potential benefits and risks to individual health. • Consider the evidence base needed to substantiate the clinical appli- cation of stem cell technologies. • Evaluate legal hurdles for establishing standards and criteria to gov- ern stem cell trials and treatments. • Discuss potential solutions for assuring the quality of stem cell offerings. 2 The workshop agenda, speaker biographical sketches, the full statement of task, a list of registered attendees, and a glossary of terms can be found in Appendixes A–E.

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4 STEM CELL THERAPIES Charo said that the status of stem cell therapies is complicated by the legislative and regulatory environment in which medical therapies exist in the United States and other countries. Medicine can be regulated through formal regulatory oversight bodies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), professional licensure and disciplinary actions, accepted profes- sional practices, professional society certifications, and medical malprac- tice law. There are a myriad of possible methods to regulate medical treatments, Charo said, “but we are finding ourselves in a situation where it is not clear that [stem cell therapies] are yet being regulated.” The FDA in particular has stated that it “is concerned that the hope that patients have for cures not yet available may leave them vulnerable to unscrupulous providers of stem cell treatments that are illegal and po- tentially harmful [and that] FDA will pursue perpetrators who expose the American public to the dangers of unapproved stem cells” (FDA, 2012). However, global enforcement can be difficult. While the majority of clin- ical trials involving stem cells are thought to take place in the United States, there are a large number being conducted elsewhere, particularly in Europe and East Asia; when examining clinical trials involving only mesenchymal stem cells (Dominici et al., 2006), East Asia is thought to be conducting the majority of studies (see Table 1-1). However, the offi- cial numbers of trials using stem cells of any kind may be skewed by underreporting of clinical trials to registries. While some trials are required to be entered into public databases, such as trials of drugs, biologics, or devices that are subject to FDA regulation, others are only voluntarily submitted and requirements vary by country.3 Another issue, Charo said, is that the marketing of treatments and products is problematic. The information that is available to the average consumer makes it difficult to discern whether a stem cell product that is being marketed has been approved by a regulatory oversight body or even if it has ever been studied. One common practice, Charo said, is to describe products as being less than minimally manipulated4 in order to 3 Entering clinical trial information into a registry does not imply endorsement by the regulatory authority of the region in which the trial is taking place. In the United States, registration requirements are described in Section 801 of the Food and Drug Administra- tion Amendments Act. 4 Minimally manipulated is defined as being produced by “processing that does not alter the relevant biological characteristics of cells or tissues” (see 21 CFR 1271.3, revised as of April 1, 2013).

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INTRODUCTION AND THEMES OF THE WORKSHOP 5 avoid being under the direct jurisdiction of the FDA. Clinics and compa- nies will also claim that journal articles and studies substantiate their claims, while listing elsewhere on their sites that they do not promise that the treatments work. “It is a very narrow line that we are trying to walk here,” Charo said. Patients are potentially being exposed to treatments that are not proven, not approved, not regulated, and possibly dangerous. Yet people also need to be informed that stem cell therapies have great potential, that clinical trials are under way, and that regenerative medicine bears tre- mendous promise for the future. TABLE 1-1 Number of Clinical Trials Under Way Using Stem Cells Clinical Trials Clinical Trials Using Country/Region Using Stem Cells Mesenchymal Stem Cells United States 2,532 73 Europe 993 98 East Asia (including China) 375 122 Canada 194 6 Middle East 172 33 Pacifica 90 8 India 62 16 South America 55 10 Southeast Asia 42 11 Russia 30 7 Central America 28 3 Japan 26 4 Mexico 24 0 Africa 19 8 SOURCE: Data drawn from a search of ClinicalTrials.gov using the terms “stem cells” or “mesenchymal stem cells” (as of March 11, 2014).

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6 STEM CELL THERAPIES THEMES OF THE WORKSHOP Over the course of the day, several broad topics emerged that were the focus of discussions. Although these points of emphasis should not be seen as consensus conclusions of the workshop, according to several participants, they may warrant further consideration as the fields of stem cell research and regenerative medicine move forward. These points of emphasis include: Regulatory uncertainty: The best ways to regulate stem cell therapies remain unclear. Stem cells have characteristics that distinguish them from drugs, biologics, or medical devices. Researchers have not yet ac- cumulated the considerable body of science that will be needed to estab- lish regulations that will enable the development and delivery of safe and effective stem cell treatments. Differing regulatory mechanisms: Countries have taken different approaches to the regulation of stem cell research and therapies, and en- forcement of existing regulations also differs. As a result, patients who are willing and able to travel from one country to another can access treatments that are not available in their home countries. Advertising strategies: In an effort to attract patients, clinics offering stem cell therapies have engaged in advertising on the Internet and else- where which is often misleading. This advertising can lead patients to spend large amounts of money on treatments that may not be effective and may even be harmful. Honoring the needs and autonomy of patients: Patients are frustrated at not being able to access potentially effective stem cell treatments, some of which are being studied in clinical trials and some of which are not. While governments have an obligation to protect patients from ineffec- tive therapies and fraudulent advertising, public policies could also reflect the needs of patients and their autonomy in making medical decisions. Generating needed information: Governments, professional associa- tions, patient groups, and other organizations all can help generate the information needed to develop effective regulations and allow patients to make informed choices. Self-regulation by the providers of stem cell therapies also could help protect patients and the legitimacy of stem cell research and therapies.

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INTRODUCTION AND THEMES OF THE WORKSHOP 7 ORGANIZATION OF THE REPORT Chapter 2 of this summary of the workshop provides an overview of what is known and what is unknown about stem cell therapies, with a particular focus on the kinds of promises being made to patients. Chapter 3 looks specifically at the experiences of patients who have opted for stem cell therapies and their reasons for making the choices they did. Chapter 4 examines the regulatory processes used in five different coun- tries to examine the commonalities and differences among the approach- es that national governments are taking to stem cell research and treatments. Chapter 5 discusses the roles of professional societies in edu- cating physicians and patients. Finally, Chapter 6 discusses important challenges, evidence gaps, and possible paths forward to make safe and effective stem cell treatments available as quickly as possible.

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