Review and comparison of clinical evidence submitted to support European Medicines Agency market authorization of orphan-designated oncological treatments

Clinical trials for treatments indicated for orphan diseases may be limited due to the low prevalence of such diseases; this can result in implications for both regulatory and health economic perspectives. This study assessed the pivotal clinical evidence packages submitted to support applications for European Medicines Agency (EMA) marketing authorizations for treatments for orphan conditions, in relation to the size of the eligible patient population.

Approved treatments for EMA-designated orphan conditions (defined as life-threatening or chronically debilitating conditions that affect ≤5/10,000 people) were identified from the EMA web site. All treatments reviewed were included in anatomical therapeutic chemical (ATC) category L (antineoplastic and immunomodulating drugs): this category was selected because it is the largest ATC category, containing almost 50 % of all approved orphan-designated products. Treatments were reviewed if they had been approved within the past 7 years and had been evaluated in a controlled trial using at least one survival-based clinical endpoint. Treatments were compared in terms of patient-years (accumulated duration of follow-up), the number of patients in the pivotal trials and disease prevalence.

As of 1 February 2014, 68 treatments had been approved for orphan-designated conditions, of which 30 belonged to ATC category L and 14 met all inclusion criteria. The number of patients in the pivotal trials ranged from 162 to 846 (median 485). In terms of patient-years, the longest duration of follow-up was seen in the pivotal trial of mifamurtide in osteosarcoma, which had 4068 patient-years; excluding this trial, follow-up ranged from 308 to 2906 patient-years (median 1796 years). Osteosarcoma had the second smallest eligible patient population (0.5/10,000 persons) of the reviewed treatments.

Clinical trials of orphan treatments are often limited by low patient numbers and inadequate follow-up. Pooling of expertise in single centres and the establishment of rare disease reference networks and patient registries may facilitate appropriate trial design for orphan-designated treatments. This analysis found that the pivotal clinical trial for mifamurtide in osteosarcoma had the largest number of patient-years of follow-up, despite a small eligible patient population, showing that it is possible to conduct studies with an adequate patient population size and duration of follow-up in patient-years, and a comparative design with clinical, survival-based, endpoints.