CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 90 NUMBER 6 | DECEMBER 2011 791 nature publishing group STATE ART Regulatory decisions related to approvals for new drugs or review of marketing authorizations for currently available drugs require careful consideration of both the benefts and risks of the drug in question. Although simple in principle, this analy- sis is ofen challenging in practice. Clinical risks and benefts may be very heterogeneous, making direct assessment of ofsets impossible. For example, a drug that provides substantial symp- tomatic beneft to a high percentage of patients may also have an extremely rare serious adverse efect. How rare does “rare” need to be, and how serious can the adverse efect be before it ofsets the drug’s symptomatic benefts? Beneft–risk models are useful tools for analyzing potential benefts and risks associated with an intervention, product, or behavior. Recently, this approach has been applied to pre- scription drugs in the academic literature and in proposals by regulators. 1–5 Although the potential of these models has been appreciated, they have not yet achieved wide application in the context of regulatory decision making. Nonprescription drugs are available to consumers without a mandatory evaluation by a health-care professional. The beneft–risk calculus for nonprescription drugs shares many of the considerations that apply to prescription drugs; however, the nonprescription setting raises unique issues with respect to both benefts and risks. It may be argued that there are clinical benefts of a nonprescription status for drugs because consumers can thereby have improved access to efective drugs. However, in the nonprescription setting, the consumer is responsible for a range of decisions about the drug’s use, including recognizing the appropriate indication; using an appropriate dosage regi- men with respect to amount, frequency, and duration of use; and seeking expert assistance if adverse events develop or if the underlying condition does not respond or worsens. 6,7 Regulatory analysis requires explicit recognition and consideration of the incremental benefts and risks that diferentiate nonprescrip- tion status from prescription status. Tis analysis may be better informed through the use of beneft–risk models that are able to incorporate these novel considerations. Appropriate beneft– risk tools have the potential to assist manufacturers during drug development and regulators during the review process. Tis article discusses the beneft and risk domains associ- ated with nonprescription drugs and proposes a value-tree tool for identifying relevant beneft–risk attributes for such drugs. Te utility of this tool is illustrated by applying a version of the International Risk Governance Council (IRGC) frame- work 8 to the beneft–risk assessment of nonprescription drugs. Importantly, the discussed approach to incorporating the unique 1 Department of Medicine, Harbor–UCLA Medical Center, Torrance, California, USA; 2 Department of Geography, King’s College London, London, UK; 3 Research Center for Risk Governance and Sustainable Technology Development (ZIRN), University of Stuttgart, Stuttgart, Germany. Correspondence: EP Brass (ebrass@ucla.edu) Received 19 July 2011; accepted 26 August 2011; advance online publication 2 November 2011. doi:10.1038/clpt.2011.231 Improving the Decision-Making Process for Nonprescription Drugs: A Framework for Benefit–Risk Assessment EP Brass 1 , R Lofstedt 2 and O Renn 3 Nonprescription drugs pose unique challenges to regulators. The fact that the barriers to access are lower for nonprescription drugs as compared with prescription drugs may permit additional consumers to obtain effective drugs. However, the use of these drugs by consumers in the absence of supervision by a health-care professional may result in unacceptable rates of misuse and suboptimal clinical outcomes. A value-tree method is proposed that defines important benefit and risk domains relevant to nonprescription drugs. This value tree can be used to comprehensively identify product-specific attributes in each domain and can also support formal benefit–risk assessment using a variety of tools. This is illustrated here, using a modification of the International Risk Governance Council (IRGC) framework, a flexible tool previously applied in a number of fields, which systematizes an approach to issue review, early alignment of stakeholders, evaluation, and risk mitigation/management. The proposed approach has the potential to provide structured, transparent tools for regulatory decision making for nonprescription drugs.