The volume and complexity of information about individual patients is greatly increasing with use of electronic records and personal devices. Potential effects on medical product development in the context of this wealth of real-world data could be numerous and varied, ranging from the ability to determine both large-scale and patient-specific effects of treatments to the ability to assess how therapeutics affect patients' lives through measurement of lifestyle changes. In October 2016, the National Academies of Sciences, Engineering, and Medicine held a workshop to facilitate dialogue among stakeholders about the opportunities and challenges for incorporating real-world evidence into all stages in the process for the generation and evaluation of therapeutics. Participants explored unmet stakeholder needs and opportunities to generate new kinds of evidence that meet those needs. This publication summarizes the presentations and discussions from the workshop. Table of Contents Front Matter 1 Introduction 2 Improving Evidence Generation for Decision Making on Approval and Use of New Treatments: Some Stakeholder Priorities 3 Opportunities for Real-World Data 4 Generating and Incorporating Real-World Evidence into Medical Product Development and Evaluation: Building from Successful Case Studies 5 Potential Strategies for a Way Forward Appendix A: Bibliography Appendix B: Workshop Agenda Appendix C: Participant Biographies Appendix D: Discussion Paper: Real-World Evidence to Guide theApproval and Use of New Treatments

Since the 2014 Ebola outbreak many public- and private-sector leaders have seen a need for improved management of global public health emergencies. The effects of the Ebola epidemic go well beyond the three hardest-hit countries and beyond the health sector. Education, child protection, commerce, transportation, and human rights have all suffered. The consequences and lethality of Ebola have increased interest in coordinated global response to infectious threats, many of which could disrupt global health and commerce far more than the recent outbreak. In order to explore the potential for improving international management and response to outbreaks the National Academy of Medicine agreed to manage an international, independent, evidence-based, authoritative, multistakeholder expert commission. As part of this effort, the Institute of Medicine convened four workshops in summer of 2015 to inform the commission report. The presentations and discussions from the Workshop on Research and Development of Medical Products are summarized in this report. Table of Contents Front Matter 1 Introduction 2 Models and Incentives for Engagement 3 Discovery Research 4 Development 5 Convergence of Regulatory Expectations, Review, and Approval 6 Manufacturing, Stockpiling, and Distribution 7 Critical Considerations for Facilitating Medical Product Research and Development 8 Crosscutting Themes and Closing Remarks Appendix A: References Appendix B: Workshop Statement of Task Appendix C: Workshop Agenda Appendix D: Workshop Speaker Biographies

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

The field of endeavors known as "regulatory science" has grown out of the need to link and integrate knowledge within and among basic science research, clinical research, clinical medicine, and other specific scientific disciplines whose focus, aggregation, and ultimate implementation could inform biomedical product development and regulatory decision making. Substantial efforts have been devoted to defining regulatory science and communicating its value and role across the scientific and regulatory ecosystems. Investments are also being made in technology infrastructure, regulatory systems, and workforce development to support and advance this burgeoning discipline. In October 2015, the National Academies of Sciences, Engineering, and Medicine held a public workshop to facilitate dialogue among stakeholders about the current state and scope of regulatory science, opportunities to address barriers to the discipline's success, and avenues for fostering collaboration across sectors. Participants explored key needs for strengthening the discipline of regulatory science, including considering what are the core components of regulatory science infrastructure to foster innovation in medical product development. This report summarizes the presentations and discussions from the workshop. Table of Contents Front Matter 1 Introduction 2 Characterizing the Regulatory Science Landscape 3 Regulatory Science Applications: Using Case Studies to Focus on Approaches to Advance the Discipline 4 Regulatory Science Infrastructure and Workforce 5 Challenges and Opportunities in Regulatory Science Appendix A: Bibliography Appendix B: Workshop Agenda Appendix C: Participant Biographies

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 development and application of regulatory science - which FDA has defined as the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products - calls for a well-trained, scientifically engaged, and motivated workforce. FDA faces challenges in retaining regulatory scientists and providing them with opportunities for professional development. In the private sector, advancement of innovative regulatory science in drug development has not always been clearly defined, well coordinated, or connected to the needs of the agency. As a follow-up to a 2010 workshop, the IOM held a workshop on September 20-21, 2011, to provide a format for establishing a specific agenda to implement the vision and principles relating to a regulatory science workforce and disciplinary infrastructure as discussed in the 2010 workshop. Table of Contents Front Matter 1 Introduction 2 The Importance of Innovative Regulatory Science 3 Defining a Discipline of Regulatory Science and Core Competencies for Its Workforce 4 Education and Training of a Regulatory Science Workforce 5 Career Paths Within Academia and Industry 6 International Applications of Regulatory Science 7 Collaborative Models and New Paradigms for Supporting Regulatory Science Research and Practice References Appendix A: Workshop Agenda Appendix B: Participant Biographies

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.

Advances in technologies and knowledge are creating new avenues for research and opportunities for the discovery and clinical development of innovative therapies and diagnostics. However, despite these opportunities, only a small fraction of investigational products are successfully developed into cures and therapies that can be accessed by patients. One response to the ever-widening gap between the number and promise of basic scientific discoveries and the translation of those discoveries into therapies is a renewed emphasis on collaborative approaches among federal agencies, academia, and industry, all directed at the advancement of the drug development enterprise. The newly developed Cures Acceleration Network (CAN)-a part of the National Center for Advancing Translational Sciences (NCATS) within the National Institutes of Health (NIH)-has the potential to catalyze widespread changes in NCATS, NIH, and the drug development ecosystem in general. On June 4-5, 2012, the IOM Forum on Drug Discovery, Development, and Translation held, at the request of NCATS, a workshop-bringing together members of federal government agencies, the private sector, academia, and advocacy groups-to explore options and opportunities in the implementation of CAN. Accelerating the Development of New Drugs and Diagnostics: Maximizing the Impact of the Cures Acceleration Network: Workshop Summary summarizes the workshop. Table of Contents Front Matter 1 Introduction 2 Approaches to Accelerating Translational Science 3 Application of Matching Authority 4 Application of Flexible Research Authority 5 Situating CAN Within the Drug Development Ecosystem 6 Final Reflections on Ways to Maximize the Goals of CAN References Appendix A: Workshop Agenda Appendix B: Public Health Service Act, Title IV - National Institutes of Health Appendix C: Participant Biographies

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

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

Whether or not the United States has safe and effective medical countermeasures-such as vaccines, drugs, and diagnostic tools-available for use during a disaster can mean the difference between life and death for many Americans. The Food and Drug Administration (FDA) and the scientific community at large could benefit from improved scientific tools and analytic techniques to undertake the complex scientific evaluation and decision making needed to make essential medical countermeasures available. At the request of FDA, the Institute of Medicine (IOM) held a workshop to examine methods to improve the development, evaluation, approval, and regulation of medical countermeasures. During public health emergencies such as influenza or chemical, biological, radiological/nuclear (CBRN) attacks, safe and effective vaccines, treatments, and other medical countermeasures are essential to protecting national security and the well being of the public. Advancing Regulatory Science for Medical Countermeasure Development examines current medical countermeasures, and investigates the future of research and development in this area. Convened on March 29-30, 2011, this workshop identified regulatory science tools and methods that are available or under development, as well as major gaps in currently available regulatory science tools. Advancing Regulatory Science for Medical Countermeasure Development is a valuable resource for federal agencies including the Food and Drug Administration (FDA), the Department of Health and Human Services (HHS), the Department of Defense (DoD), as well as health professionals, and public and private health organizations. Table of Contents Front Matter 1 Introduction 2 MCM Enterprise and Stakeholder Perspectives 3 Cutting-Edge Efforts to Advance MCM Regulatory Science 4 MCM Regulatory Science Needs for At-Risk Populations 5 Crosscutting Themes and Future Directions 6 Closing Remarks References Appendix A: Workshop Agenda Appendix B: Participant Biographies