FDA approval, clinical trial evidence, efficacy, epidemiology, and price for non-orphan and ultra-rare, rare, and common orphan cancer drug indications: cross sectional analysis.

OBJECTIVE

To analyze the US Food and Drug Administration (FDA) approval, trials, unmet needs, benefit, and pricing of ultra-rare (<6600 affected US citizens), rare (6600-200 000 citizens), and common (>200 000 citizens) orphan cancer drug indications and non-orphan cancer drug indications.

DESIGN

Cross sectional analysis.

SETTING

Data from Drugs@FDA, FDA labels, Global Burden of Disease study, and Medicare and Medicaid.

POPULATION

170 FDA approved drugs across 455 cancer indications between 2000 and 2022.

MAIN OUTCOME MEASURES

Comparison of non-orphan and ultra-rare, rare, and common orphan indications regarding regulatory approval, trials, epidemiology, and price. Hazard ratios for overall survival and progression-free survival were meta-analyzed.

RESULTS

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. Drugs for ultra-rare orphan indications were more frequently first in class (76% 48% 38% 42%; P<0.001), monotherapies (88% 69% 72% 55%; P=0.001), for hematologic cancers (76% 66% 0% 0%; P<0.001), and supported by smaller trials (median 85 199 286 521 patients; P<0.001), of single arm (84% 44% 28% 21%; P<0.001) phase 1/2 design (88% 45% 45% 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% 26% 12%; P<0.001), first line (77% 39% 20%; P<0.001), small molecules (80% 62% 48%; P<0.001) benefiting from quicker time to first FDA approval (median 5.7 7.1 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 0.51 0.49 0.64; P<0.001), but not overall survival benefit (0.50 0.73 0.71 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% 48% 55% 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) $33 313 $16 484 $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.

CONCLUSIONS

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. These orphan indications fill significant unmet needs, yet their approval is based on small, non-robust trials that could overestimate efficacy outcomes. A distinct ultra-orphan designation with greater financial incentives could encourage and expedite drug development for ultra-rare diseases.