Generating evidence from expanded access use of rare disease medicines: challenges and recommendations 233 11 ♠ Lastly, it should be carefully determined whether the benefits of evidence generation outweigh the additional paperwork and research strains imposed on patients and physicians - the changing nature of compassionate use programs to contribute ‘research’ in addition to ‘treatment’ has posed concerns to bioethicists.12 Ethical oversight could ensure that data collection respects the treatment intent of expanded access. POLICY RECOMMENDATIONS In this perspective we have illustrated the usage of expanded access data in rare disease medicines in scientific publications, regulatory filings, and health technology assessment. Although these data are frequently used, the role of expanded access in evidence generation, and the regulations governing data collection, are extremely divergent. The European setup of compassionate use is a patchwork of national access pathways, which may deter rather than expedite patient access to investigational medicine. We here offer several potential policy recommendations. First, we call for regulatory guidance for data collection in expanded access settings, for example by including expanded access in real-world evidence frameworks, or offering means of integrating expanded access data in the guideline on patient registries.56 This guidance should acknowledge the observational nature, suggest means for assuring data quality (remote monitoring, database requirements), and ensure that the burden placed on physicians and patients for data collection is justified by the needs for additional evidence generation. Lastly, it could highlight the types of data collection that may be most desirable, such as real-world patient demographics, dosing, or treatment adherence. For rare diseases, a more flexible approach regarding the use of expanded access data could be considered. Second, the EMA guidelines could be revised to encourage the responsible use of expanded access data. Guidelines could clarify that expanded access data cannot replace clinical trial data, but may supplement such data to inform usage in non-trial populations or to increase patient numbers in rare disease. This is consistent with other efforts to expand use of ‘real-world evidence’, or evidence derived from non-trial data sources.57 The lack of mention of efficacy data by the EMA is not in line with individual Member States’ initiatives that explicitly combine expanded access and evidence generation. Such paradoxes should be prevented and a future revision of the guidelines should include efficacy outcomes. The notion that clinical trials are the only means of obtaining reliable information does not align with the inclusion of expanded access data in decision making by the EMA: regulatory submissions have included data from expanded access programs to clarify the efficacy and safety profile of certain drugs.33 The EMA guideline from 2007 discusses expanded access ‘versus’
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