In November 2011, amid growing concerns about the future of the U.S. clinical trials enterprise and its competitiveness on the global stage, the forum convened a public workshop for stakeholders to lay out a vision for a transformed clinical trials enterprise in the United States by 2020. At the time, there was growing recognition that the clinical trials enterprise in the United States faced substantial challenges impeding the efficient and effective conduct of clinical research to support the development of new medicines and evaluate existing therapies.

Read full text of Envisioning a Transformed Clinical Trials Enterprise in the United States: Establishing an Agenda for 2020: Workshop Summary (IOM, 2012)

Reflecting back over the past decade, there have been advances in the field as well as setbacks:

Integrating Community Practice and Clinical Research
Despite efforts on the part of key stakeholders, including researchers, sponsors, government agencies, clinicians, and patients, the divide between community practice and clinical research remains. At the time of the workshop, health care was moving toward more integrated delivery systems and the widespread use of EHRs. Workshop participants called for disruptive innovation and a push for health delivery systems—along with other research, clinical, and educational entities—to develop and implement business plans that integrate research into routine clinical practice. Yet today, progress toward this goal has been limited.

Improving Public Participation in Clinical Trials
Over the past decade, tremendous advances have been made to improve public participation throughout the drug R&D lifecycle, including several laws that incorporate the voice and perspective of patients. In 2010, the Patient-Centered Outcomes Research Institute (PCORI) was established by an act of Congress to improve the quality and relevance of patient-centered evidence available to patients, caregivers, clinicians, policy makers, and other stakeholders for making better informed health decisions. The 2012 FDA Safety and Innovation Act¹ and corresponding fifth authorization of the Prescription Drug User Fee Act (PDUFA V) included provisions to enhance the role of the patient voice in the drug development process. Within the past few years, Congress passed the 21st Century Cures Act,² and the FDA Reauthorization Act of 2017,³ which included patient engagement provisions. The push for a more people-centered approach to drug R&D has led to a culture shift among public and private stakeholders. “Patient-centeredness” and “patient-focused” drug development are now part of the everyday lexicon.

Aligning Cultural and Financial Incentives
There has been significant change in the regulatory environment over the past 10 years. A modernized way of thinking in this space has improved the field of clinical trials. There has been progress when it comes to developing and implementing incentives for drug development to treat rare diseases and cancer. These improved business models have addressed unmet needs for these conditions/ diseases, but now the trials enterprise is seeing comparatively low investment in drug innovation for treating prevalent chronic conditions. With many suboptimal drugs for these conditions on the market, the current fee-for-service reimbursement system provides little incentive for the biopharmaceutical industry to invest in developing new treatments. Without sufficient investment, much of the basic biology of these diseases remains unknown, and fewer exciting breakthroughs and opportunities for publishing are furthering the waning interest in researching these conditions.

Building the Infrastructure and Workforce
The clinical trials infrastructure requires substantial resources to recruit investigators, coordinate across research sites, implement quality control systems, enroll and retain trial participants, and seek regulatory approval. Responsible sharing of clinical trial data is in the public interest and helps maximize the benefits of research for future patients and society as a whole. Collaborative approaches are needed to support the collection, management, analysis, and sharing of clinical trial data. The development and application of regulatory science calls for a well-trained, scientifically engaged, and motivated workforce. The forum has fostered the development of strategies to improve the discipline of innovative regulatory science and continues to focus attention on critical infrastructure and workforce issues. Considerable opportunities remain to improve and enhance the infrastructure supporting the clinical trials enterprise.

Sharing Clinical Research Data—A Workshop (2012)
On October 4–5, 2012, four convening bodies—the Forum on Drug Discovery, Development, and Translation; the Forum on Neuroscience and Nervous System Disorders; the National Cancer Policy Forum; and the Roundtable on Translating Genomic-Based Research for Health (now called the Roundtable on Genomics and Precision Health)—collectively hosted a workshop to examine and advance the sharing of clinical data. The workshop explored the benefits of sharing clinical research data, the barriers to such sharing, and strategies to address these barriers to facilitate the development of safe, effective therapeutics and diagnostics. Participants in the workshop discussed the importance of developing mutually beneficial partnerships in promoting data sharing, the need for data standardization to improve reliability, and how incentives are fundamental to a culture shift that recognizes the value of data sharing.

Sharing Clinical Trial Data—An Action Collaborative
A related action collaborative jointly convened by the Forum on Drug Discovery, Development, and Translation; the Forum on Neuroscience and Nervous System Disorders; the National Cancer Policy Forum; and the Roundtable on Genomics and Precision Health was launched in 2016. Through meetings with interested parties, including nonprofit funders of research, patient advocacy organizations, and data- sharing stakeholders, the action collaborative developed and refined a statement of data-sharing goals that could be incorporated into participating organizations’ funding policies. In March 2021, participants published a Viewpoint in the Journal of Participatory Medicine, “Data Sharing Goals for Nonprofit Funders of Clinical Trials.”

Real-World Evidence Generation and Evaluation of Therapeutics— A Workshop (2016)
On October 19, 2016, the forum convened a workshop to examine opportunities and challenges for incorporating real-world evidence into the evaluation of medical products. Workshop participants discussed how various sources of real-world data (e.g., claims data, patient-generated data) could be used to address unmet stakeholder needs; priorities for improving evidence generation to support decision making; barriers to incorporating real-world evidence into product development and process evaluation; and next steps to expand the role of real-world evidence in the development and evaluation of therapeutics.

Examining the Impact of Real-World Evidence on Medical Product Development—A Workshop Series (2017–2018)
Over the course of several months in 2017 and 2018, the forum hosted a series of three workshops on the generation and utilization of real-world evidence, sponsored by FDA. Each workshop in the series focused on a different topic, with workshop 1 exploring how to align incentives to support the collection of real-world data and the use of real-world evidence in health product review, payment, and delivery. Workshop 2 focused on illuminating what types of data are appropriate for what specific purposes and suggesting approaches for data collection and evidence use by developing and working through example use cases. Workshop 3 examined and suggested approaches for operationalizing real-world data collection and the use of real-world evidence.

In June 2021, some individual workshop speakers and attendees published a set of four articles in in Clinical Pharmacology & Therapeutics, which were inspired by what they learned at this workshop series and took into account lessons learned from the COVID-19 pandemic.

• “When Can We Rely on Real-World Evidence to Evaluate New Medical Treatments?” outlines the paper series’ scope, context, and the dimensions considered where real-world evidence studies may differ from traditional trials.
• “When Can We Trust Real-World Data to Evaluate New Medical Treatments?” lays out questions to help stakeholders assess potential error or bias at each step of data generation from clinical presentation (including with a device) to inclusion in a database.
• “When Are Treatment Blinding and Treatment Standardization Necessary
  in Real-World Clinical Trials?” lays out questions to help stakeholders determine whether blinding and treatment standardization may be necessary for the internal validity of a study or may distort meaningful differences between treatments in specific cases.
• “When Can Nonrandomized Studies Support Valid Inference Regarding Effectiveness or Safety of New Medical Treatments?” lays out questions to help stakeholders evaluate the potential impact of confounding or other biases on their research findings.

Improving the Drug Development Process Through Examining Late-Stage Failures—An Action Collaborative
This action collaborative examined the contributing factors in the failure of late-stage clinical product development and developed key considerations for stakeholders to improve the probability of success. Action collaborative participants conducted a literature survey as well as a series of structured informational interviews with stakeholders directly involved in late-stage therapeutic development. Results were analyzed, categorized, and presented at a meeting of action collaborative participants at which additional insights were discussed. The efforts of action collaborative participants culminated in the publication of an article in Nature Reviews Drug Discovery, “The Failure to Fail Smartly.”

Virtual Clinical Trials: Challenges and Opportunities— A Workshop (2018)
On November 28–29, 2018, the forum hosted a workshop, Virtual Clinical Trials: Challenges and Opportunities. This workshop examined the clinical trials infrastructure and potential opportunities for supporting the practical implementation of virtual clinical trials. Workshop participants discussed the inefficiencies of the existing clinical trial enterprise; the boundaries of what might be considered a virtual clinical trial; opportunities to expand access for patients; perspectives of using digital health technologies in clinical care and observational and interventional studies; impact of using digital health technologies on access and equity to clinical trials; policy landscape governing clinical trials; and possible opportunities for future action.

Mapping and Connecting the Biomedical Innovation Ecosystem—An Action Collaborative
The Mapping and Connecting the Biomedical Innovation Ecosystem action collaborative was established under the auspices of the forum to help frame, map, and synergize activities and communication across the biomedical innovation ecosystem. Action collaborative participants developed two process maps— coined the Drug Discovery, Development, and Deployment Maps (4DM)—that diagram the development of small molecules and biologics, which are digitally hosted by the National Center for Advancing Translational Sciences at NIH. The process maps served as the foundation for two complementary peer-reviewed articles released in December 2017 and co-authored by action collaborative participants to guide future dialogue and progress on this topic. “A Dynamic Map for Learning, Communicating, Navigating, and Improving Therapeutic Development” was published in Nature Reviews Drug Discovery and “Application of a Dynamic Map for Learning, Communicating, Navigating, and Improving Therapeutic Development” was simultaneously published in Clinical and Translational Science.

The Role of Digital Health Technologies in Drug Development— A Workshop (2020)
The forum and the Roundtable on Genomics and Precision Health hosted a public workshop on March 24, 2020, which provided a venue for stakeholders to discuss challenges and opportunities in using digital health technologies to improve the probability of success in drug development. The COVID-19 pandemic, which was only beginning to disrupt daily life at the time of the workshop, added a sense of urgency to the workshop discussions on practical and ethical considerations for the development and implementation of digital health technologies. Workshop participants considered key components for an evidence-based framework for applying digital health technologies toward drug R&D. Workshop participants discussed how digital health technologies could be uniquely suited to address persistent problems in drug R&D, considered barriers to implementing digital health technologies, and discussed opportunities to move the field forward.

Deriving Drug Discovery Value from Large-Scale Genetic Bioresources—A Workshop (2016)
On March 22, 2016, the forum and the Roundtable on Genomics and Precision Health convened a workshop to examine and discuss how large-scale genetic data could be used to improve the likelihood of bringing effective and targeted therapies to patients. Workshop participants assessed the current landscape of genomic- enabled drug discovery and development activities; examined enabling partnerships and better business models; and considered gaps and best practices in how data from populations could be collected with the goal of improving the drug discovery process.

Enabling Precision Medicine: The Role of Genetics in Clinical Drug Development—A Workshop (2018)
Those involved in the drug development process face challenges of efficiency and overall sustainability due in part to high research costs, lengthy development timelines, and late-stage failures. Novel clinical trial designs that enroll participants based on their genetics represent a potentially disruptive change that could improve patient outcomes, reduce costs associated with drug development, and further realize the goals of precision medicine. On March 8, 2017, the forum and the Roundtable on Genomics and Precision Health hosted a workshop that examined successes, challenges, and possible best practices for effectively using genetic information in the design and implementation of clinical trials to support the development of precision medicines, including exploring the potential advantages and disadvantages of such trials across a variety of disease areas. Workshop participants took a general, high-level approach in their examination of these issues to take a pulse of the successes that have been realized and the challenges that have been encountered, and considered how these experiences might inform the advancement of precision medicine.

Enhancing Scientific Reproducibility in Biomedical Research Through Transparent Reporting—A Workshop (2019) In collaboration with the Forum on Neuroscience and Nervous System Disorders, the National Cancer Policy Forum, and the Roundtable on Genomics and Precision Health, the forum convened a workshop on September 25–26, 2019, to examine the state of transparency in reporting biomedical research (e.g., disclosure of the availability and location of data, materials, analyses, and methodology) and to explore the possibility of improving the harmonization of guidelines across journals and funding agencies so that biomedical researchers propose and report data in a consistent manner. Workshop participants discussed the challenges and opportunities for the harmonization of guidelines for transparent reporting throughout the biomedical research lifecycle. The agenda included a panel discussion on facilitating the development of consistent guidelines (e.g., a common set of minimal reporting standards) that could be applied across journals and funders to increase transparency in proposing and reporting biomedical research. This workshop was sponsored by Cell Press, The Lancet, Nature Research, and NIH.

Advancing the Science of Patient Input on Medical Product R&D: Towards a Research Agenda—A Workshop (2018)
There is growing momentum to incorporate patient input into medical product R&D and regulatory decision-making processes. Converting traditionally anecdotal patient input to rigorous, credible evidence could better align medical product development and regulation with patient perspectives on disease experience, burden, management, and treatment. The forum convened a workshop on May 9, 2018, focused on the science of patient input for pre-market medical product R&D (including pre-discovery, discovery, pre-clinical development, and clinical development), with consideration of downstream regulatory and post-market decision making. At this workshop, subject-matter experts representing a range of disciplines examined the current state of the science, including successes and limitations of existing efforts, for soliciting and incorporating patient input in pre-market R&D; explored gaps in the knowledge base and other barriers that impede progress; and reviewed a potential framework for and components of a research agenda for addressing the gaps or barriers to realizing a science of patient input.

Drug Research and Development for Adults Across the Older Age Span— A Workshop (2020)
Despite the widespread recognition of the “graying of America,” and the need for health care among older adults, there is a dearth of information about the appropriate use of drugs in this population. Older adults are vastly underrepresented in clinical trials. Yet, older adults have higher rates of comorbidities and polypharmacy than the general population and are the majority users of many medications. Additionally, age- related physiological and pathological changes, particularly for adults over age 80, can lead to significant differences in the pharmacokinetic and pharmacodynamics of a given drug compared to the general population. There is a void in evidence-based information for making informed decisions on how to best optimize care for older adults. In collaboration with the Forum on Aging, Disability, and Independence and the National Cancer Policy Forum, the forum hosted a workshop on August 5 and 6, 2020, that discussed the challenges and opportunities in drug R&D for the over age 65 and over age 80 populations, explored barriers that impede safety and efficacy studies in these populations, and shared lessons learned and best practices for better understanding the clinical pharmacology for older adults.

Building a National Framework for the Establishment of Regulatory Science for Drug Development—A Workshop (2010)
The 2007 Institute of Medicine (IOM) report The Future of Drug Safety: Promoting and Protecting the Health of the Public identified the need for an improved science base for drug evaluation within FDA, including internal resources and extramural funding for collaboration with academia. In that same year, the FDA Science Board,⁴ at the request of Congress, reported on the agency’s need for an enhanced science base, including infrastructure development, multisector collaboration, and an expanded workforce capable of addressing the rapidly evolving science of drug discovery and development. In 2008, the forum held a public workshop to explore the science of drug regulation, focusing on the gap between leading-edge technologies of drug development and FDA’s capacity to adapt its process of regulatory evaluation to these technologies. Together, the results of these efforts suggested a widening gap between scientific developments in areas relevant to FDA’s mission and its ability to address these innovations, as well as a lack of understanding among the public, policy makers, and the agency of what is required to fill this gap. To address these concerns, the forum convened a public workshop on February 26, 2010, to examine the state of the science of drug regulation and consider approaches for enhancing the scientific basis of regulatory decision making. Workshop participants explored the concept of regulatory science, examined how it could be used to improve regulatory decision making, and considered alternative mechanisms and institutional frameworks for its development and application.

Strengthening a Workforce for Innovative Regulatory Science in Therapeutics Development—A Workshop (2011)
The development and application of regulatory science—which FDA 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. On September 20–21, 2011, the forum held a public workshop that considered the opportunities and needs for advancing innovation in the discipline of regulatory science for therapeutics development through an interdisciplinary regulatory science workforce. Workshop participants discussed the core components of a robust discipline of regulatory science; deliberated on the key competencies for a regulatory science workforce; and examined the needs and opportunities to promote training, career development, and collaborative approaches to sustain and nurture a workforce in innovative regulatory science.

Clinical trials research has changed dramatically over the past decade. The biological, physical, and digital spheres are merging; clinical research and health care are at a critical juncture; and new technologies enable the collection of data in real-world settings. These opportunities hold great promise for advancing our understanding of health maintenance and prevention, disease progression, and developing new therapies for patients. At the same time, the clinical research enterprise faces continued and mounting pressures, strained from all sides by rising costs, an evolving regulatory and economic landscape, increasing clinical trial complexity, difficulties in the recruitment and retention of research participants, and a clinical research workforce that is under tremendous stress. Some, but not all, of these challenges and opportunities were predicted in the 2011 forum-hosted workshop Envisioning a Transformed Clinical Trials Enterprise in the United States: Establishing an Agenda for 2020. There is now a need for stakeholders from across the clinical research lifecycle, including patients, caregivers, sponsors, technologists, regulators, practitioners, and researchers, to examine the challenges and setbacks, lessons learned, and advances from the past decade and consider the challenges and opportunities that may be coming over the next 10 years. On January 26, February 9, March 24, and May 11, 2021, the forum will convene a public workshop to discuss how to better integrate community practice and clinical trials, improve patient engagement in clinical trials, align cultural and financial incentives, and better support the clinical trials infrastructure. The workshop will provide a venue to consider a transformed clinical trial enterprise for 2030 and discuss the goals and key priorities for advancing a clinical trials enterprise that is more efficient, effective, person-centered, inclusive, and integrated into the health care delivery system of 2030.

As the U.S. population ages, the overall number of individuals diagnosed with cancer is increasing and older adults also account for a growing proportion of both cancer diagnoses and cancer deaths. Clinicians, along with patients with cancer, and their families rely on clinical research for information on the potential benefits and harms of different treatment options so that they can make informed treatment decisions that are consistent with the patients’ needs, values, and preferences. However, the evidence base for older adults with cancer is limited by a pervasive underrepresentation of this population in cancer clinical trials. To begin to address these issues, the forum, along with the National Cancer Policy Forum and the Forum on Aging, Disability, and Independence, will host an FDA-sponsored, public workshop on January 22, 25, and 27, 2021. This workshop will aim to illuminate a path forward in generating meaningful evidence for the treatment of older adults with cancer.

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Chronic diseases such as heart disease, stroke, cancer, and diabetes are the leading cause of death and disability among Americans and a major factor in the nation’s rapidly increasing health care costs. At present, 6 in 10 U.S. adults live with at least one chronic disease, and 4 in 10 have two or more. However, despite the human and financial costs of chronic diseases, investment in the disorders has not kept pace with the need. On February 22 and March 1 and 8, 2021, the forum will host a public workshop to examine and highlight the bottlenecks to innovation in drug R&D for prevalent chronic diseases and consider the challenges and opportunities for spurring drug R&D in this space.

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The use and misuse of antibiotics contributes to the rise in drug-resistant bacteria—a serious and worsening threat to human health. Addressing the problem of antibiotic resistance requires measures to spur innovation and ensure the prudent use of existing drugs. Rapid diagnostics can play an important role in avoiding the unnecessary use of antimicrobials by providing clinicians with the right information at the right time to help them make decisions about appropriate drug treatment for patients, have the capacity to support early detection and diagnosis of drugresistant bacterial infections, enable disease surveillance, and help prevent disease spread. Participants in this public workshop will discuss the current landscape of rapid diagnostics to address antibiotic resistance, consider the challenges and opportunities for spurring innovation, and discuss practical next steps for accelerating the development of new diagnostic tools.

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The cost and duration of clinical trials have escalated dramatically in the past 20 years, hampering the introduction of new therapies; driving recruitment to developing countries; and raising questions about generalizability, data quality, and participant protections. While some sites in the United States are extremely efficient in launching new trials and in identifying participants, many still suffer from long delays in contracting and Institutional Review Board approvals, and enrollment targets are frequently missed. The protections of research participants are variably applied, with the processes for consent and adherence to Good Clinical Practice suboptimal at some sites, and standards for training and site-level preparedness are variable. The consequences are borne by NIH, foundations, and industry alike, with the ultimate impact on the public.

This action collaborative seeks to accelerate progress in the improvement of the national clinical trials infrastructure. To date, the action collaborative has drawn together a group of diverse stakeholders for four in-person meetings (December 2012, August 2013, March 2014, and September 2018). Action collaborative participants published a discussion paper, which summarized their perspectives on the concept of clinical trial site accreditation and laid out a framework and principles for developing clinical trial site standards. In addition, the action collaborative has undertaken an activity to collect, analyze, and prioritize a set of core site standards that could be considered for broad application by research sponsors.

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There is growing momentum to incorporate patient input into medical product R&D and regulatory decision-making processes. Converting traditionally anecdotal patient input to rigorous, credible evidence for use by a broad range of stakeholders—including academic and clinical researchers, medical product developers, patient/disease advocacy groups, and regulatory decision makers—could better align medical product development and regulation with patient perspectives on disease experience, burden, management, and treatment. Many efforts have been launched to advance a science of patient input. However, there is a critical need to identify gaps in the knowledge base and other barriers that impede progress and develop a research agenda for addressing them.

This action collaborative was established to identify gaps in the knowledge base and other barriers that impede progress in advancing the science of patient input. Stakeholders came together for a meeting of the action collaborative on July 30, 2019, to discuss and prioritize gaps and barriers that should be included in a research agenda to advance the science of patient input. In 2021, action collaborative participants will work toward the publication of this activity.

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Half of all Americans live with at least one chronic disease,⁶ such as heart disease, cancer, stroke, or diabetes. These and other chronic diseases are the leading cause of death and disability in the United States and are a leading driver of health care costs, with approximately 90 percent of health care expenditures related to chronic conditions.^{7, 8} Yet, investment in these leading causes of death and disability, other than cancer, has not reflected this burden. The 2020 outbreak of coronavirus disease 2019 (COVID-19) may further exacerbate the health disparities associated with high- impact prevalent chronic diseases.

The goal of this action collaborative is to examine and highlight the bottlenecks to drug R&D for highly prevalent chronic diseases and develop a set of key considerations and potential strategies for spurring innovation. In 2021, action collaborative participants will develop and distribute a structured, qualitative questionnaire to key stakeholders. Results will be synthesized and used to inform next steps for the action collaborative.

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