Box 1. “Orphan drug” Designation
CML, TKI-resistant CML, gastrointestinal hemorrhages, chronically debilitating disease, CML-CP, infections, bone marrow dysfunction, MAIC
GASTROINTESTINAL HEMORRHAGES, INFECTIONS, DISSEMINATED INTRAVASCULAR COAGULATION, EMA, CML
“Orphan drugs” are medicinal products intended for rare indications for which research and development are incentivized by the regulatory bodies to increase product profitability. The EMA defines “orphan drugs” accordant with 3 major criteria: (1) the prevalence of the “orphan condition” is less than 5 in 10 000 EU citizens; (2) the “orphan condition” is a life-threatening or chronically debilitating disease; and (3) the “orphan drug” must be of significant benefit in the treatment of the “orphan condition.” Regarding the latter criterium, significant benefit denotes drug-induced improvement of patient outcome as opposed to all other available treatment for the same “orphan condition,” and it also considers complete or partial overlap of the therapeutic indication for the “orphan drug” as compared to other products authorized for the same “orphan condition.” The main incentive for obtaining “orphan drug” designation at the EMA is 10 years of market exclusivity for the “orphan condition” after receiving market authorization. Other incentives offered by the EMA are (a) “orphan drug” tailored scientific advice known as protocol assistance, (b) central assessment of the “orphan drug” for the entire EU, (c) fee reductions on regulatory activities, (d) administrative and procedural assistance for micro-, small-, and ­medium-sized enterprises, and (e) an additional 2 years of market exclusivity for “orphan drugs” with an approved pediatric investigation plan. As an example for “orphan drug” designation assessment at the EMA, asciminib was assessed for the scope of the treatment of CML according to the 3 major criteria. First, the estimate of CML prevalence was noted to be 1.4 in 10,000 EU citizens, with a highest reported national prevalence of 2 in 10,000 Belgian citizens. Second, CML was considered both a life-threatening and chronically debilitating disease due to the presence and/or risk of bone marrow dysfunction, intracranial, and gastrointestinal hemorrhages, disseminated intravascular coagulation, and severe infections. Third, the evidence for significant benefit of asciminib over bosutinib was provided in the comparative trial the applicant submitted in their marketing authorization application. The significant benefit of asciminib over ponatinib, another TKI-resistant CML drug, was assessed with matching-adjusted indirect comparison (MAIC), as there was no direct comparison trial conducted by the sponsor. The MAIC analysis compared data of the ASCEMBL trial (asciminib) with 203 patients with CML-CP from the PACE (ponatinib) trial, and MAIC-adjusted MMR differences were non-significant at 24 and 48 weeks. Moreover, subgroup analysis of the ASCEMBL trial was indicative for efficacy of asciminib in patients previously treated with ponatinib. Therefore, significant benefit of asciminib was established in patients with CML-CP especially for those resistant to or intolerant of ponatinib. In conclusion, all the requirements for “orphan drug” designation were met for the treatment of asciminib in patients with CML, and market protection was granted for 10 years in the EU.