Table 4.

Evidence of sample sizes setting of pivotal trials

	Randomized controlled trials	Open trials
Target sample sizes with statistical evidence	Agalsidase alfaa (26 patients) Canakinumaba (31 patients) Galsulfasea (39 patients) Agalsidase betaa (58 patients) Risedronatea (120 patients) Elosulfase alfaa (176 patients) Sunitinib b (191 patients) Tafamidisc (125 patients) Basiliximabc (376 patients) Dornase alphac (968 patients)	Cinacalceta (46 patients) Tamibarotene b (39 patients) Nilotinibb (282 patients)
Feasibility	Idursulfasea (96 patients) Dasatinibb (150 patients) Eculizumabc (87 patients)	Phenylbutyratea (11 patients) Heminb (2 patients) Vorinostatb (6 patients) Cladribineb (9 patients) Freeze-dried concentrated human activated protein C c (3 patients) Metreleptin c (4 patients) Drying polyethylene glycol treatment human immunoglobulin c (7 patients) Infliximab c (Behcet’s disease) (12 patients) Tocilizumab c (Ewing sarcoma) (28 patients)

Classification according to trial design/case setting basis in the pivotal trials of the ultra-orphan drugs. ^aMetabolic drugs, ^bAnticancer drugs, ^cdrugs other than metabolic drugs and anticancer drugs. (patients) behind the drug name: real sample sizes (when there were controls, the sample sizes of the total of controls and this drug is given). Italics were not approved outside of Japan at the time of Japanese approval