(259) Marketing Authorisation Pathways and Clinical Evidence Supporting Approval of Orphan Medicinal Products in EU Between January 2015 and October 2021

Publication Number: 590

Background: Generating evidence for the safety and efficacy of treatments indicated for orphan diseases may be challenging due to the low prevalence of these diseases.

Objectives: The objective of this study is to characterise the clinical evidence supporting marketing authorisation (MA) of orphan medicinal products and explore if there is an association between rarity of disease and type of MA given and the strength of clinical evidence respectively.

Methods: We identified all medicinal products with MA with an orphan designation (OD) approved between Jan 2015 and Oct 2021, cross-referencing the EMA “download table of all EPARs for human and veterinary medicines” and the “EMA download table of all orphan designation” on the EMA homepage. All included ODs were categorised as rare or ultra-rare based on the prevalence of the condition (rare: ≤5/10,000 and > 1/100,000 and ultra-rare: ≤1/100,000) as stated in the public summary of opinion on ODs. We retrieved the European Public Assessment Report (EPAR) for all included OD. We collected information about the initial marketing authorisation type (standard MA, conditional MA (CMA) or exceptional circumstances MA (EC MA)), as well as information about pivotal (main) clinical studies supporting the MA. Information collected includes number of pivotal trials, study design (randomisation, blinding) and use of clinical or surrogate endpoints. Association between the rarity of the disease and MA type and use of blinded randomised clinical trials, respectively, was tested using Chi-square test of independence.

Results: 109 ODs were granted MA during the period; 76% were for ultra-rare diseases, and 24% for rare diseases. An absolute majority (72%) was granted standard MA, 17% CMA, and 11% EC MA. There was no statistically significant difference in MA type between rare and ultra-rare diseases (p-value = 0.3285). Hundred-twenty-four pivotal clinical trials supported the authorisation of the 109 ODs. All but 3 OD (for ultra-rare diseases) was supported by min. one (max 4) pivotal clinical trial. Half (52%) were double-blinded randomised clinical trials and 47% of the trials used a clinical endpoint; 53% only used a surrogate endpoint as a primary endpoint. There was no significant difference between rare and ultra-rare diseases and study design (p-value = 0.3704) or between rarity of disease and use of clinical endpoints (p-value = 0.979).

Conclusions: Most orphan medical product authorisations between Jan 2015 and Oct 2021 were granted for ultra-rare diseases, and most were granted a standard MA. No association between type of MA or clinical evidence supporting MA and rarity of disease was found.