Based on an analysis of 170 FDA-approved drugs across 455 cancer indications from 2000 to 2022, researchers conclude that a “distinct ultra-orphan designation with greater financial incentives could encourage and expedite drug development for ultra-rare diseases.” While “the Orphan Drug Act of 1983 incentivizes development of drugs not only for rare diseases but also for ultra-rare diseases and subsets of common diseases,” the authors write that “these orphan indications fill significant unmet needs, yet their approval is based on small, non-robust trials that could overestimate efficacy outcomes.”
“161 non-orphan and 294 orphan cancer drug indications were identified, of which 25 were approved for ultra-rare diseases, 205 for rare diseases, and 64 for common diseases,” the authors write. “Drugs for ultra-rare orphan indications were more frequently first in class (76% v 48% v 38% v 42%; P <0.001), monotherapies (88% v 69% v 72% v 55%; P=0.001), for hematologic cancers (76% v 66% v 0% v 0%; P <0.001), and supported by smaller trials (median 85 v 199 v 286 v 521 patients; P <0.001), of single arm (84% v 44% v28% v 21%; P <0.001) phase 1/2 design (88% v 45% v 45% v 27%; P <0.001) compared with rare and common orphan indications and non-orphan indications. Drugs for common orphan indications were more often biomarker directed (69% v 26% v 12%; P <0.001), first line (77% v 39% v 20%; P <0.001), small molecules (80% v 62% v 48%; P <0.001) benefiting from quicker time to first FDA approval (median 5.7 v7.1 v 8.9 years; P = 0.02) than those for rare and ultra-rare orphan indications. Drugs for ultra-rare, rare, and common orphan indications offered a significantly greater progression-free survival benefit (hazard ratio 0.53 v 0.51 v 0.49 v 0.64; P <0.001), but not overall survival benefit (0.50 v 0.73 v 0.71 v 0.74; P = 0.06), than non-orphans. In single arm trials, tumor response rates were greater for drugs for ultra-rare orphan indications than for rare or common orphan indications and non-orphan indications (objective response rate 57% v 48% v 55% v 33%; P <0.001). Disease incidence/prevalence, five year survival, and the number of available treatments were lower, whereas disability adjusted life years per patient were higher, for ultra-rare orphan indications compared with rare or common indications and non-orphan indications. For 147 on-patent drugs with available data in 2023, monthly prices were higher for ultra-rare orphan indications than for rare or common orphan indications and non-orphan indications ($70,128 (£55 971; €63,370) v $33,313 v $16,484 v $14,508; P <0.001). For 48 on-patent drugs with available longitudinal data from 2005 to 2023, prices increased by 94% for drugs for orphan indications and 50% for drugs for non-orphan indications on average.”