This proposal on Nanodiagnostics and Nanotherapeutics:Building Research Ethics and Oversight responds to RFA-OD-009-0003, addressing Challenge Area "02: Bioethics" and Challenge Topic "Unique Ethical Issues Posed by Emerging Technologies," as set forth in 02-OD (OSP)-101. The ability to manipulate atoms and molecules at the nanoscale has catalyzed the emerging field of nanomedicine. While many biological phenomena occur at the nanoscale, "nanomedicine" denotes material fabricated at the scale of 1-100 nanometers (nm) to take advantage of novel properties (biological, optical, thermal, chemical, and mechanical) that manifest at the nanoscale. A focal area of development is nanodiagnostics and nanotherapeutics. These fields use nanotechnology to develop nanoscale tools for in vitro diagnostics, in vivo imaging agents, drugs and therapies, targeted drug delivery systems, nanoparticle and other nanoscale gene delivery vectors, biomaterials for enhanced tissue engineering, and multi-function medical devices. Nanomedicine poses enormous challenges for human subjects research and oversight particularly because the health, safety, and environmental impacts of nanomaterials are largely unknown and researchers are struggling to characterize these materials and develop adequate toxicology and assessment tools. Despite these unknowns, research on nanodiagnostics and nanotherapeutics is already being conducted with human participants. Institutional Review Boards (IRBs), Data Monitoring Committees (DMCs) and Data Safety Monitoring Boards (DSMBs), funders such as the National Institutes of Health (NIH), and oversight authorities at NIH, the Food and Drug Administration (FDA), and Office for Human Research Protections (OHRP) are already facing acute challenges posed by nanomedicine research, but without systematic guidance on how to address those challenges. Indeed, the FDA has already approved some nanomedical products for use in human beings. Work is urgently needed to address what substantive changes to the rules governing human subjects research and what procedural changes to research oversight are necessary. This 2-year project will examine current and emerging nanomedicine research on drugs, devices, and gene therapy in order to map the issues raised by nanodiagnostic and nanotherapeutic research and oversight and formulate much-needed guidance. We will collect and analyze existing guidance on human subjects research and oversight by the NIH, FDA, and OHRP in nanotherapeutics and nanodiagnostics as well as existing policy analysis. We will use that to inform normative work generating the first systematic recommendations to ensure adequate protections and oversight for human participants in nanomedicine research. This process will involve collaboration among Investigators and Working Group members who are directly involved in the science, medicine, policy, law, and ethics of nanotechnology. This project will have major impact by providing the first systematic and comprehensive guidance on the ethical conduct and oversight of human subjects research on nanotherapeutics and nanodiagnostics. Outcomes will be: (1) an assessment of publicly available documents indicating how researchers, IRBs, DMCs/DSMBs, NIH, FDA, OHRP, and relevant professional societies are currently approaching the ethics of human subjects nanomedicine research;(2) an assessment of how NIH (including the Office of Biotechnology Activities (OBA) and the Recombinant DNA Advisory Committee (RAC)), FDA, and OHRP are approaching the oversight of human subjects nanomedicine research;(3) the first comprehensive and systematic recommendations on the ethics and oversight of human subjects nanomedicine research, to be authored by the Investigators after critique by the Working Group;(4) additional individually authored papers by members of the Working Group;(5) a public conference with videotape archived for free public access;(6) a comprehensive bibliography;and (7) rich web-based resources. This proposed project will serve the goals of ARRA by creating 4 jobs and significantly augmenting a fifth to aid in retention of that job. This project brings together top experts on nanomedicine, biomedical engineering, law, policy, and bioethics to produce the first systematic and comprehensive recommendations on how to protect human participants in research on nanodiagnostics and nanotherapeutics, including drugs, devices, and gene therapy using nonviral nano- vectors. Research in these nano-fields is burgeoning, with research on human participants under way, but current research ethics and oversight have not yet adequately addressed key concerns including: difficulty predicting human response from animal data, uncertainty about how to assess risks, concerns about both participant and third-party safety both short-term and long-term, and challenges obtaining informed consent. The project group will use normative, empirical, and policy analysis to evaluate current approaches to nanomedicine research ethics and oversight, including at NIH, FDA, and OHRP, generating much-needed recommendations on ethics standards and oversight processes.