Development of a universal benefit-risk assessment framework and its application for regulatory agencies

The assessment of medicines has moved from efficacy and safety to that of a benefit-risk balance and regulatory agencies and pharmaceutical companies are improving their processes in order to achieve greater consistency and transparency in decision-making. However, their efforts are largely independent and do not address the lack of consistency in decisions by different countries, albeit for the same medicine, resulting in the potential inaccessibility of important medicines. The aim of this study was the development and validation of a universal benefit-risk framework for use by regulatory authorities. A questionnaire, specifically developed for this study, was used to evaluate the current approaches to benefit-risk assessment of medicines by 14 regulatory agencies and 24 pharmaceutical companies. None of the 11 agencies (79%) and 20 companies (83%) that responded used a fully quantitative approach, but the majority used a qualitative system for benefit-risk assessment. The development of a universal benefit-risk framework for use by both regulators and industry, with the involvement of all stakeholders, was supported by the study participants. A comparison of the existing benefit-risk assessment frameworks used by agencies and companies identified the common elements. As no major differences were observed, an 8-step universal framework was developed which incorporated the other frameworks. To support the framework in the assessment of benefits and risks, a template for documenting the benefit-risk decision together with a user manual was also developed. Four regulatory agencies conducted a retrospective pilot study to investigate the feasibility of this framework, the benefit-risk template and user manual. Subsequently, a prospective study was conducted by TGA of Australia, Health Canada and HSA of Singapore. The agencies found the benefit-risk template was ‘fit for purpose’ in terms of the relevance of information supporting the benefit-risk decision, the documentation and communication and the relative importance and values of the benefits and risks. The results showed that the benefit-risk summary template was adequate to document benefits and risks, relevant summaries and ii conclusions for the emerging markets. The applicability and validity of the summary component of the benefit-risk template was evaluated by sixteen HSA clinical reviewers in a retrospective study. They found that the BR Summary Template was adequate to document benefits, risks, relevant summaries and conclusions. However, a revision of the BR Summary Template should include technical improvements and more details of safety information. The BR Summary Template was thought to be a useful tool for communicating benefit-risk decisions to a variety of stakeholders. The formats of publicly available reports from major regulatory agencies were compared and found to be generally similar. When compared to the BR Template, the listing of benefits and risks, assigning of weights and values, visualisation and a more detailed, systematic standardised structure were found to be absent. This research has demonstrated that the 8-step universal framework is of value for the assessment of benefits and risks of medicines by regulatory agencies and the template was found to be useful for documenting and communicating benefit-risk decisions.