Background: Biomedical research has important social and economic value. It helps to promote individual and population health, boosts competitiveness and innovative capacity, and thereby contributes to economic growth. Yet, biomedical research exposes study participants to risks. Research also poses risks to public health when the science is poor. The ethical acceptability of research therefore critically depends on protecting participants’ rights and safety, while promoting the scientific and social value of the research. Research regulations are designed to ensure that these requirements are met. -- Patient organizations, investigators, sponsors, and others are increasingly dissatisfied with the existing regulatory framework. Many call for a “risk-based” system of research oversight that matches various safeguards – including independent ethical review and safety monitoring and reporting – to the level of risk posed by the research (e.g., revision of the EU Clinical Trials Directive). However, it remains unclear what such a system should look like.Objectives: 1) To address the ethical questions raised by risk-based research regulations, including the stratification of research risks and the relation between risk, consent, and the scientific and social value of the research. 2) To develop an ethical framework for risk-based research regulations.Methods: Interdisciplinary study that combines conceptual and normative analysis, policy analysis, and expert consultation.Target audience: Policymakers, research regulators, research ethicists, and others interested in the ethics and regulation of risk.Impact: By calibrating safeguards and protections to the level of risk posed by a study, the envisioned framework will help to promote valuable research consistent with adequate subject protection. This is a prerequisite for responsible progress in health. The project will inform current policy and ethical debates both on a national and international level.