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

Abstract

BackgroundClinical 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.MethodsApproved 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.ResultsAs 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.ConclusionsClinical 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.

The Comparative Effectiveness of Innovative Treatments for Cancer (CEIT-Cancer) project: Rationale and design of the database and the collection of evidence available at approval of novel drugs

“… FDA 2008–2012 Not described/Unclear Solid tumors and hematologic malignancies x x Wang and Kesselheim (2015) [ 40 ] To characterize the types of comparators and endpoints used in efficacy trials for approvals of supplemental indications, compared with the data supporting these drugs’ originally approved indications. FDA 2005–2014 Supplemental only Any disease or medical condition [e] x x x Winstone et al (2015) [ 41 ] To characterize the clinical trial evidence of orphan drugs. EMA 2006–2014 Not described/Unclear Solid tumors and hematologic malignancies [f] x x x Downing et al (2014) [ 6 ] To characterize pivotal efficacy trials for newly approved novel therapeutic agents.…”

Characteristics of Single Pivotal Trials Supporting Regulatory Approvals of Novel Non‐orphan, Non‐oncology Drugs in the European Union and United States from 2012−2016

“…Our focus on non‐oncology, non‐orphan novel therapeutic drugs was based on two considerations. First, the regulatory requirements for approval of drugs to treat cancer and orphan indications seem to be subject to a higher degree of regulatory flexibility, and the evidence supporting approval of these drugs has already been widely debated . Second, we wished to gain insight into the regulatory precedence for approvals based on a single pivotal trial for drugs intended to treat more prevalent and not immediately life‐threatening diseases knowing that the outcome would potentially represent a very heterogeneous group of drugs and therapeutic areas.…”

“…It has been widely debated whether regulators should accept a higher level of uncertainty concerning benefits and risks for life‐threatening or severely debilitating conditions with high medical needs, especially in the case of rare diseases . Several analyses of marketing authorizations of oncology and orphan drugs suggest that the approvals are often based on limited evidence of efficacy . As such, it has been argued that there is a widening gap in the regulatory requirements for approval of such drugs compared with other disease areas …”

Analysis of Orphan Drugs Marketed in Spain during the Period 2010- 2015: Epidemiological, Clinical and Economic Characteristics

“…The majority of the clinical trials of orphan drugs approved in Spain were phase III (57.7%), randomized (79.1%) and/or double blind (54.2%), differing little from non-orphan drug trials in terms of the methodologies used [26,27].…”