Each year, the individuals and organizations in the U.S. organ donation, procurement, allocation, and distribution system work together to provide transplants to many thousands of people, but thousands more die before getting a transplant due to the ongoing shortage of deceased donor organs and inequitable access to transplant waiting lists. Realizing the Promise of Equity in the Organ Transplantation System, a new consensus study report from the National Academies of Sciences, Engineering, and Medicine?s Committee on A Fairer and More Equitable, Cost-Effective, and Transparent System of Donor Organ Procurement, Allocation, and Distribution, provides expert recommendations to improve fairness, equity, transparency, and cost-effectiveness in the donor organ system. Table of Contents Front Matter Summary 1 Introduction and Study Context 2 The U.S. Organ Transplantation System and Opportunities for Improvement 3 Foundations for a Trustworthy Deceased Donor Organ Transplantation System 4 Confronting and Eliminating Inequities in the Organ Transplantation System 5 Saving More Lives and Enhancing Equity with Deceased Donor Organ Allocation Policies 6 Improving Procurement, Acceptance, and Use of Deceased Donor Organs 7 Measuring and Improving System Performance Appendix A: Public Meeting Agendas Appendix B: IOM and National Academies Solid Organ Transplantation Reports Appendix C: Biographical Sketches of Committee Members and Staff

There is growing recognition that the United States' clinical trials enterprise (CTE) faces great challenges. There is a gap between what is desired - where medical care is provided solely based on high quality evidence - and the reality - where there is limited capacity to generate timely and practical evidence for drug development and to support medical treatment decisions. With the need for transforming the CTE in the U.S. becoming more pressing, the IOM Forum on Drug Discovery, Development, and Translation held a two-day workshop in November 2011, bringing together leaders in research and health care. The workshop focused on how to transform the CTE and discussed a vision to make the enterprise more efficient, effective, and fully integrated into the health care system. Key issue areas addressed at the workshop included: the development of a robust clinical trials workforce, the alignment of cultural and financial incentives for clinical trials, and the creation of a sustainable infrastructure to support a transformed CTE. This document summarizes the workshop. Table of Contents Front Matter 1 Introduction 2 Integrating Community Practice and Clinical Trials 3 Improving Public Participation in Clinical Trials 4 Creating a New Business Model for Clinical Trials 5 Building an Infrastructure to Support Clinical Trials 6 Suggesting an Agenda for Transforming Elements of the Clinical Trials Enterprise References Appendix A: Workshop Agenda Appendix B: Participant Biographies Appendix C: Registered Workshop Attendees Appendix D: Discussion Paper: The Clinical Trials Enterprise in the United States: A Call for Disruptive Innovation Appendix E: Discussion Paper: Developing a Robust Clinical Trials Workforce Appendix F: Discussion Paper: Transforming the Economics of Clinical Trials Appendix G: Discussion Paper: Developing a Clinical Trials Infrastructure Appendix H: Discussion Paper: Canadian Strategy on Patient-Oriented Research Appendix I: Discussion Paper: Health Research as a Public Good Appendix J: Discussion Paper: Novel Ways to Get Good Trial Data: The UK Experience Appendix K: IOM Staff Paper: Context and Glossary of Select Terms Associated with the Clinical Trials Enterprise

Despite the extensive body of evidence that informs regulatory decisions on pharmaceutical products, significant uncertainties persist, including the underlying variability in human biology, factors associated with the chemistry of a drug, and limitations in the research and clinical trial process itself that might limit the generalizability of results. As a result, regulatory reviewers are consistently required to draw conclusions about a drug's safety and efficacy from imperfect data. Efforts are underway within the drug development community to enhance the evaluation and communication of the benefits and risks associated with pharmaceutical products, aimed at increasing the predictability, transparency, and efficiency of pharmaceutical regulatory decision making. Effectively communicating regulatory decisions necessarily includes explanation of the impact of uncertainty on decision making. On February 12 and May 12, 2014, the Institute of Medicine's Forum on Drug Discovery, Development, and Translation held public workshops to advance the development of more systematic and structured approaches to characterize and communicate the sources of uncertainty in the assessment of benefits and risks, and to consider their implications for pharmaceutical regulatory decisions. Workshop presentations and discussions on February 12 were convened to explore the science of identifying and characterizing uncertainty in scientific evidence and approaches to translate uncertainties into decisions that reflect the values of stakeholders. The May 12 workshop presentations and discussions explored tools and approaches to communicating about scientific uncertainties to a range of stakeholders in the drug development process. Characterizing and Communicating Uncertainty in the Assessment of Benefits and Risks of Pharmaceutical Products summarizes the presentation and discussion of both events. This report explores potential analytical and communication approaches and identifies key considerations on their development, evaluation, and incorporation into pharmaceutical benefit- risk assessment throughout the entire drug development lifecycle. Table of Contents Front Matter 1 Introduction 2 Identifying and Characterizing Uncertainty 3 The Regulators' Challenge 4 Basic Methodologies and Applications for Understanding and Evaluating Uncertainty 5 Communicating Uncertainty 6 Final Reflections on Ways to Characterize and Communicate Uncertainty References Appendix A: Workshop Agenda Appendix B: FDA Case Studies Appendix C: Bibliography Appendix D: Participant Biographies

The question of whether and under what circumstances terminally ill patients should be able to access life-ending medications with the aid of a physician is receiving increasing attention as a matter of public opinion and of public policy. Ethicists, clinicians, patients, and their families debate whether physician-assisted death ought to be a legal option for patients. While public opinion is divided and public policy debates include moral, ethical, and policy considerations, a demand for physician-assisted death persists among some patients, and the inconsistent legal terrain leaves a number of questions and challenges for health care providers to navigate when presented with patients considering or requesting physician-assisted death. To discuss what is known and not known empirically about the practice of physician-assisted death, the National Academies of Sciences, Engineering, and Medicine convened a 2-day workshop in Washington, DC, on February 12?13, 2018. This publication summarizes the presentations and discussions from the workshop. Table of Contents Front Matter 1 Introduction 2 Conceptual, Legal, and Ethical Considerations in Physician-Assisted Death 3 Experiences with and Reflections on Physician-Assisted Death in the United States 4 Experiences with and Reflections on Physician-Assisted Death Internationally 5 Implementation and Practice of Physician-Assisted Death 6 Physician-Assisted Death in the Context of Long-Term Services and Supports, Palliative Care, and Hospice 7 Reflections on the Workshop and Evidentiary Gaps Appendix A: Workshop Agenda Appendix B: Biographical Sketches of Workshop Speakers and Planning Committee Members

Multidrug-resistant tuberculosis (TB) is caused by bacteria resistant to isoniazid and rifampicin, the two most effective first-line anti-TB drugs, originally developed and introduced in the 1950 and 1960s. Since 2008, the Forum on Drug Discovery, Development, and Translation of the Institute of Medicine has hosted or co-hosted six domestic and international workshops addressing the global crisis of drug-resistant TB, with special attention to the BRICS countries - Brazil, Russia, India, China, and South Africa. The Global Crisis of Drug-Resistant Tuberculosis and Leadership of China and the BRICS is the summary of a workshop convened to address the current status of drug-resistant TB globally and in China. This report considers lessons learned from high burden countries; highlights global challenges to controlling the spread of drug-resistant strains; and discusses innovative strategies to advance and harmonize local and international efforts to prevent and treat drug-resistant TB. Additionally, the report examines the problem of MDR TB and emergent TB strains that are potentially untreatable with drugs available and considers the critical leadership role of the BRICS countries in addressing the threats and opportunities in drug-resistant TB.

To effectively treat patients diagnosed with drug-resistant (DR) tuberculosis (TB) and protect the population from further transmission of this infectious disease, an uninterrupted supply of quality-assured (QA), second-line anti-TB drugs (SLDs) is necessary. Patients diagnosed with multidrug-resistant tuberculosis (MDR TB)-a disease caused by strains of Mycobacterium tuberculosis (M.tb.) resistant to two primary TB drugs (isoniazid and rifampicin)-face lengthy treatment regimens of 2 years or more with daily, directly observed treatment (DOT) with SLDs that are less potent, more toxic, and more expensive than those used to treat drug-susceptible TB. From 2000 to 2009, only 0.2-0.5 percent of the estimated 5 million MDR TB cases globally were treated with drugs of known quality and in programs capable of delivering appropriate care (Keshavjee, 2012). The vast majority of MDR TB patients either died from lack of treatment or contributed to the spread of MDR TB in their communities. A strengthened global supply chain for SLDs could save lives by consistently delivering high quality medicines to more of the people who need them. This public workshop explored innovative solutions to the problem of how to get the right SLDs for MDR TB to people who critically need them. More specifically, the workshop examined current problems and potential opportunities for coordinated international efforts to ensure that a reliable and affordable supply of high-quality SLDs is available. Developing and Strengthening the Global Supply Chain for Second-Line Drugs for Multidrug-Resistant Tuberculosis: Workshop Summary covers the objectives of the workshop, which were to review: -To what extent and in what ways current mechanisms are or are not effectively accomplishing what is needed, including consideration of bottlenecks. -The advantages and disadvantages of centralization in the management of the global drug supply chain, and potential decentralized approaches to improve operations of the supply chain. -What can be learned from case studies and examples from other diseases (e.g., the Affordable Medicines Facility-malaria (AMFm) and the U.S. President's Emergency Plan for AIDS Relief [PEPFAR]) - The current allocation of responsibilities and roles of the private (including industry and nonprofit public health organizations) and public sectors, and examination of opportunities for enhancing and optimizing collaboration -Identification of potential innovative solutions to the problem Table of Contents Front Matter 1 Introduction 2 Logistics, Supply, and Demand 3 Financing of MDR TB SLDs 4 Innovative Suggestions and Potential Solutions References Appendix A: Workshop Agenda Appendix B: Participant Biographies Appendix C: Registered Workshop Attendees

Randomized clinical trials (RCTs) are often referred to as the "gold standard" of clinical research. However, in its current state, the U.S. clinical trials enterprise faces substantial challenges to the efficient and effective conduct of research. Streamlined approaches to RCTs, such as large simple trials (LSTs), may provide opportunities for progress on these challenges. Clinical trials support the development of new medical products and the evaluation of existing products by generating knowledge about safety and efficacy in pre- and post-marketing settings and serve to inform medical decision making and medical product development. Although well-designed and -implemented clinical trials can provide robust evidence, a gap exists between the evidence needs of a continuously learning health system, in which all medical decisions are based on the best available evidence, and the reality, in which the generation of timely and practical evidence faces significant barriers. Large Simple Trials and Knowledge Generation in a Learning Health System is the summary of a workshop convened by the Institute of Medicine's Roundtable on Value & Science-Driven Health Care and the Forum on Drug Discovery, Development, and Translation. Experts from a wide range of disciplines-including health information technology, research funding, clinical research methods, statistics, patients, product development, medical product regulation, and clinical outcomes research-met to marshal a better understanding of the issues, options, and approaches to accelerating the use of LSTs. This publication summarizes discussions on the potential of LSTs to improve the speed and practicality of knowledge generation for medical decision making and medical product development, including efficacy and effectiveness assessments, in a continuously learning health system. Large Simple Trials and Knowledge Generation in a Learning Health System explores acceleration of the use of LSTs to improve the speed and practicality of knowledge generation for medical decision making and medical product development; considers the concepts of LST design, examples of successful LSTs, the relative advantages of LSTs, and the infrastructure needed to build LST capacity as a routine function of care; identifies structural, cultural, and regulatory barriers hindering the development of an enhanced LST capacity; discusses needs and strategies in building public demand for and participation in LSTs; and considers near-term strategies for accelerating progress in the uptake of LSTs in the United States. Table of Contents Front Matter 1 Introduction 2 Large Simple Trials Now and Looking Forward 3 Examples of Large Simple Trials 4 Medical Product Regulatory Issues 5 Infrastructure Needs and Opportunities 6 Ethical and Privacy Policy Issues 7 Research Partner Perspectives 8 The Randomized Evaluations of Accepted Choices in Treatment Trials 9 Strategies Going Forward Appendix A: Workshop Agenda Appendix B: Biographical Sketches of Speakers

An estimated 8.8 million people fell ill with tuberculosis (TB) in 2010 and 1.4 million died from the disease. Although antibiotics to treat TB were developed in the 1950s and are effective against a majority of TB cases, resistance to these antibiotics has emerged over the years, resulting in the growing spread of multidrug-resistant (MDR) TB. Due to challenges in timely and accurate diagnosis of drug-resistant TB, length and tolerability of treatment regimens, and expense of second-line anti-TB drugs, effectively controlling the disease requires complex public health interventions. The IOM Forum on Drug Discovery, Development, and Translation held three international workshops to gather information from local experts around the world on the threat of drug resistant TB and how the challenges it presents can be met. Workshops were held in South Africa and Russia in 2010. The third workshop was held April 18-19, 2011, in New Delhi, India, in collaboration with the Indian National Science Academy and the Indian Council of Medical Research. The aim of the workshop was to highlight key challenges to controlling the spread of drug-resistant strains of TB in India and to discuss strategies for advancing and integrating local and international efforts to prevent and treat drug-resistant TB. This document summarizes the workshop. Table of Contents Front Matter 1 Introduction 2 Drug-Resistant TB in India 3 The Global Burden of Drug-Resistant TB 4 Preventing Transmission of Drug-Resistant TB 5 Detecting Drug Resistance and Strengthening Laboratory Capacity 6 Addressing TB and Drug-Resistant TB in Vulnerable Populations 7 Combating Drug-Resistant TB Through PublicPrivate Collaboration and Innovative Approaches 8 Confronting Challenges to the Supply Chain for SecondLine Drugs 9 Creating a Blueprint for Action References Appendix A: Workshop Agenda Appendix B: Summary of a Joint Meeting of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Indian Biomedical Research Agencies, Held April 20-21, 2011, New Delhi, India Appendix C: Participant Biographies

Clinical trials provide essential information needed to turn basic medical research findings into patient treatments. New treatments must be studied in large numbers of humans to find out whether they are effective and to assess any harm that may arise from treatment. There is growing recognition among many stakeholders that the U.S. clinical trials enterprise is unable to keep pace with the national demand for research results. The IOM, along with the Mount Sinai School of Medicine, held a workshop June 27-28, 2011, to engage stakeholders and experts in a discussion about possible solutions to improve public engagement in clinical trials. Table of Contents Front Matter 1 Introduction 2 Framing the Problem 3 Recruitment Challenges in Clinical Trials for Different Diseases and Conditions 4 Models for Public Engagement 5 Messages and Methods for Public Engagement 6 The Media 7 Novel Clinical Trial Designs 8 The Health System's Structure and Culture 9 Toward a Patient-Centered Strategy for Clinical Trials References Appendix A: Workshop Agenda Appendix B: The Clinical Trials Process Appendix C: Participant Biographies

An ideal health care 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. 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. To address these issues and better understand the current state of clinical research in the United States, the Institute of Medicine's (IOM) Forum on Drug Discovery, Development, and Translation held a 2-day workshop entitled Transforming Clinical Research in the United States. The workshop, summarized in this volume, laid the foundation for a broader initiative of the Forum addressing different aspects of clinical research. Future Forum plans include 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 strategies and collaborative activities to facilitate more robust public engagement in the clinical research enterprise. Table of Contents Front Matter 1 Introduction 2 The State of Clinical Research in the United States: An Overview 3 Challenges in Clinical Research 4 Clinical Trials in Cardiovascular Disease 5 Clinical Trials in Depression 6 Clinical Trials in Cancer 7 Clinical Trials in Diabetes 8 Building a Robust Clinical Trials Infrastructure References Appendix A Agenda Appendix B Participant Biographies