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

• Published in: BMJ (Online) Vol. 381; p. e073242
• Main Authors: Michaeli, Thomas, Jürges, Hendrik, Michaeli, Daniel Tobias
• Format: Journal Article
• Language: English
• Published: England 09-05-2023
• Subjects: Aged; Antineoplastic Agents; Cross-Sectional Studies; Humans; Medicare; Neoplasms - drug therapy; Neoplasms - epidemiology; Orphan Drug Production; Rare Diseases - drug therapy; United States - epidemiology; United States Food and Drug Administration; United States
• ISSN: 1756-1833
• DOI: 10.1136/bmj-2022-073242

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.
Cross sectional analysis.
Data from Drugs@FDA, FDA labels, Global Burden of Disease study, and Medicare and Medicaid.
170 FDA approved drugs across 455 cancer indications between 2000 and 2022.
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.
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.
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.