Which clinical trial designs and statistical approaches have been used in assessments of orphan maintenance by the European Medicines Agency between 2012 and 2022? A cross-sectional study.

objectivesIn the European Union, a new orphan medicinal product must demonstrate 'significant benefit' over approved medicinal products targeting the same indication. To demonstrate a significant benefit, comparisons between the new product and the already approved medicinal products-either directly by a head-to-head comparison within a clinical trial or indirectly as a cross-trial comparison-are necessary. In this study, we investigate the types of trial designs and statistical approaches used for demonstrating a significant benefit of a new orphan medicinal product against approved comparators used between 2012 and 2022.

designThis is a cross-sectional study based on the European Medicines Agency's 'orphan maintenance' assessment documents between 2012 and 2022. All documents were manually reviewed to extract structured data on the following outcome measures:For every comparison between a new orphan medicinal product and a comparator used for demonstrating a significant benefit as part of an orphan maintenance procedure, we recorded the type and design of the data source and the type of statistical methodology used for the comparison.

resultsWe identified 151 EMA orphan maintenance procedures with a positive decision that required the demonstration of a significant benefit. Within these 151 procedures, 418 comparisons between medicinal products were identified. Indirect comparisons are the most common approach for comparing the new orphan medicinal product to a relevant comparator (44%, 182/418), followed by qualitative comparisons (39%, 162/418) and direct comparisons (18%, 74/418). Among the indirect comparisons, naive side-by-side comparisons are most often used (71%, 129/182), whereas inferential approaches that adjust for population differences and quantify the uncertainty of the comparison are used less often (29%, 53/182). Although there is no clear time trend in the prevalence of any specific comparison type, we find that inferential indirect comparison methods approximately doubled between the first and second half of the reviewed time frame.

conclusionsIndirect comparisons play an important role in demonstrating a significant benefit in the assessment of orphan products. Further work is needed to evaluate the appropriateness of different methodologies.