Toward a New Era of Trust and Transparency in Clinical Trials.

Clinical trials are the most publicly visible component of the biomedical research enterprise, from the potential human application of novel laboratory findings to the generation of robust evidence about treatments or preventive interventions in routine clinical care. These trials are also the point at which biomedical research most directly engages human participants—dedicated volunteers who trust investigators to uphold the highest standards of scientific rigor and ethical oversight. While clinical trials have evolved and improved over time— producing impressive advances in diagnosis, treatment, and prevention—there are still major challenges. Therefore, fundamental changes are needed to reflect science and society’s movement to increase efficiency, accountability, and transparency in clinical research. As the largest public funder of clinical trials in the United States, currently investing more than $3 billion each year, the National Institutes of Health (NIH) takes its stewardship of the nation’s clinical trial enterprise very seriously. Therefore, NIH must ensure that supported trials investigate a mission-relevant question that is of high priority, do not needlessly duplicate previously conducted trials (in contrast to providing needed replication), and have the highest likelihood to advance knowledge and improve health. To achieve this goal, a number of challenges in the design, efficiency, and reporting of clinical trials need to be addressed.1,2 For example, too often clinical trials are overly complex, have small sample sizes, rely on surrogate end points that lack clinical relevance, have unrealistic accrual rates, and have inadequate budgets. Of particular concern is the existence of trials from which the results are never published or data submitted to a public database.3,4 Therefore, the NIH has launched a multifaceted effort to improve the quality and efficiency of clinical trials, an effort that is focused on a variety of key points along the “lifespan” of a clinical trial (eFigure in the Supplement). These initiatives will reengineer the process by which clinical investigators develop ideas for new trials, how NIH reviews and selects clinical trials for support and oversees the progress of the research, and how results and aggregate data are shared broadly and rapidly. Specifically, these changes are aimed at enhancing the application and award processes, increasing NIH’s ability to assess the merits and feasibility of clinical trial applications; improving oversight and transparency; and increasing the sharing of clinical trial results. In combination, these initiatives are intended to ensure rigor and efficiency in the US clinical trial enterprise. As a crucial first step, NIH will require Good Clinical Practice (GCP) training for investigators and NIH staff responsible for conducting or overseeing clinical trials. The aim is to help ensure that all involved in the clinical trial enterprise have the appropriate knowledge about the design, conduct, monitoring, recording, analysis, and reporting of clinical trials. While GCP training on its own may not be sufficient, it provides a consistent and highquality standard. Another important change at the beginning of the clinical trial lifecycle is a new NIH policy that will require all applications for clinical trials to be submitted in response to clinical trial–specific Funding Opportunity Announcements (FOAs). This will mean that applications including one or more clinical trials will no longer be accepted in response to parent funding announcements, which are broad FOAs that allow researchers to submit investigator-initiated applications without specific elements appropriate to describe and evaluate a trial. Under this policy, NIH trial applications will need to contain specific information about protocols and other information necessary for effective peer and programmatic review. In addition, clinical trial–specific FOAs will include review criteria that focus on the rationale, design, and operational and analysis plans, all of which will inform assessments of proposed studies. Peer review of NIH clinical trial applications must be conducted by study sections with appropriate expertise, such as clinical trialists, biostatisticians, and pharmacologists, as well as the basic science experts needed to evaluate the scientific rigor of relevant preclinical data provided. The advisory councils of NIH’s institutes and centers (ICs) also will be responsible for ensuring that clinical trials supported by their respective ICs address these important priorities. After funding decisions have been made, terms specific to clinical trial research will be incorporated into Notices of Award to remind awardees of their responsibilities, including timely sharing of research results. Inconsistent information submitted to the NIH for clinical trial applications and to the US Food and Drug Administration (FDA) under the investigational new drug (IND) application process has long been recognized as a source of delays and inefficiencies. To assist NIH-funded investigators to plan their studies in a way that is also consistent with the FDA IND process, the NIH is encouraging the use of a clinical trial protocol template that was developed through a collaboration between NIH and FDA5 and that meets International Council for Harmonisation (ICH) E6 Good Clinical Practice Guidance.5 Use of the protocol template will help ensure that investigators prepare protocols that contain all the information necessary to enable efficient and timely review by institutional review boards (IRBs) and to be in compliance with FDA IND application regulations. VIEWPOINT