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

Abstract

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% 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% v 28% 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 v 7.1 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.

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.

Fig 1

Time from investigational new drug application (IND) to first Food and Drug Administration (FDA) approval for non-orphan anticancer drugs and orphan anticancer drugs for ultra-rare, rare, and common diseases. Top: cumulative incidence of first FDA approval for anticancer drugs with orphan and non-orphan designation. Bottom: cumulative incidence of first FDA approval for anticancer drugs with orphan designations for common, rare, and ultra-rare diseases. Orphan indications were stratified according to number of affected US citizens into common (>200 000), rare (200 000-6600), or ultra-rare (<6600). Only drugs receiving FDA approval within 12 years of IND are shown. CI=confidence interval

Fig 2

Meta-analysis of overall survival (OS) for anticancer drugs for ultra-rare, rare, and common orphan indications and non-orphan indications approved by Food and Drug Administration (FDA) from 2000 to 2022. Treatment outcomes were meta-analyzed for randomized controlled trials. Orphan indications were stratified according to number of affected US citizens into common (>200 000), rare (200 000-6600), or ultra-rare (<6600). CI=confidence interval; IQR=interquartile range. *Cochran’s Q test for subgroup differences. †Kruskal-Wallis-tests

Fig 3

Meta-analysis of progression-free survival (PFS) for anticancer drugs for ultra-rare, rare, and common orphan indications and non-orphan indications approved by Food and Drug Administration (FDA) from 2000 to 2022. Treatment outcomes were meta-analyzed for randomized controlled trials. Orphan indications were stratified according to number of affected US citizens into common (>200 000), rare (200 000-6600), or ultra-rare (<6600). CI=confidence interval; IQR=interquartile range. *Cochran’s Q test for subgroup differences. †Kruskal-Wallis-tests

Fig 4

Meta-analysis of tumor response for anticancer drugs for ultra-rare, rare, and common orphan indications and non-orphan indications approved by Food and Drug Administration (FDA) from 2000 to 2022. Treatment outcomes were meta-analyzed for randomized controlled trials. Orphan indications were stratified according to number of affected US citizens into common (>200 000), rare (200 000-6600), or ultra-rare (<6600). Continuity adjustment of 0.5 for control arms with 0 responders was applied. CI=confidence interval; IQR=interquartile range. *Cochran’s Q test for subgroup differences. †Kruskal-Wallis-tests

Fig 5

Meta-analysis of tumor response for anticancer drugs for ultra-rare, rare, and common orphan indications and non-orphan indications approved by Food and Drug Administration (FDA) from 2000 to 2022, showing average tumor response rates measured in single arm trials. Orphan indications were stratified according to number of affected US citizens into common (>200 000), rare (200 000-6600), or ultra-rare (<6600). Continuity adjustment of 0.5 for control arms with 0 responders was applied. CI=confidence interval; IQR=interquartile range, *Cochran’s Q test for subgroup differences. †Kruskal-Wallis-tests

Fig 6

Prices for anticancer drugs for orphan and non-orphan indications from 2005 to 2023. Top: monthly prices of drugs with and without orphan designation for original Food and Drug Administration (FDA) indication are compared in 2023. Bars represent means with 95% confidence intervals. Bottom: mean price change of orphan and non-orphan drugs is compared from 2005 until 2023. Lines illustrate price indices with baseline set in 2005. Inflation was measured by consumer price index (CPI)

Fig 7

Prices for anticancer drugs for ultra-rare, rare, and common orphan indications from 2005 to 2023. Top: monthly prices of drugs with non-orphan and ultra-rare, rare, and common orphan designation for original Food and Drug Administration (FDA) indication are compared in 2023. Bars represent means with 95% confidence intervals. Bottom: mean price changes for non-orphan and ultra-rare, common, and rare orphan drugs from 2005 until 2023. Lines illustrate price indices with baseline set in 2005. Inflation was measured by consumer price index (CPI). Orphan indications were stratified according to the number of affected US citizens into common (>200 000), rare (200 000-6600), or ultra-rare (<6600)