Table 2.
Description of European Public Assessment Reports (EPARs) of orphan medicinal products
| Conditions with single acute episodes | Conditions with recurrent acute episodes | Chronic conditions with stable or slow progression | Chronic progressive conditions led by one system/organ | Chronic progressive conditions led by multiple system/organs | Chronic staged conditions | Total | |
|---|---|---|---|---|---|---|---|
| No of EPARs | n = 23 | n = 9 | n = 13 | n = 19 | n = 23 | n = 38 | n = 125 |
| Ultra rare condition (< 1/100.000) | 1 (4.3%) | 2 (22.2%) | 1 (7.1%) | 3 (16.7%) | 9 (39.1%) | 0 (0.0%) | 16 (12.8%) |
| Type of evidence supporting the MAA approval | |||||||
| Bibliographic report | 3 (13.0%) | 1 (11.1%) | 2 (14.3%) | 1 (5.6%) | 1 (4.3%) | 1 (2.6%) | 9 (7.2%) |
| Compassionate use | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (5.6%) | 1 (4.3%) | 0 (0.0%) | 2 (1.6%) |
| Observational retrospective | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 4 (17.4%) | 0 (0.0%) | 4 (3.2%) |
| Clinical trial | 20 (87.0%) | 8 (88.9%) | 12 (85.7%) | 16 (88.9%) | 17 (73.9%) | 37 (97.4%) | 110 (88.0%) |
| N of MAA based on clinical trials | n = 20 | n = 8 | n = 12 | n = 16 | n = 17 | n = 37 | n = 110 |
| > = 2 clinical trials | 7 (35.0%) | 5 (62.5%) | 9 (75.0%) | 6 (37.5%) | 4 (23.5%) | 7 (18.9%) | 38 (34.5%) |
| No. of pivotal clinical trials | |||||||
| Mean (SD) | 1.4 (0.5) | 1.6 (0.5) | 2.3 (1.1) | 1.6 (1.1) | 1.2 (0.4) | 1.2 (0.5) | 1.4 (0.7) |
| Median (P25-P75) | 1.0 (1.0–2.0) | 2.0 (1.0–2.0) | 2.0 (1.5–3.0) | 1.0 (1.0–2.0) | 1.0 (1.0–1.0) | 1.0 (1.0–1.0) | 1.0 (1.0–2.0) |
| No. of supportive trials | |||||||
| Mean (SD) | 3.6 (3.3) | 4.3 (3.5) | 3.7 (2.2) | 2.2 (1.6) | 2.9 (1.5) | 2.9 (1.7) | 3.1 (2.3) |
| Median (P25-P75) | 3.0 (1.0–5.0) | 2.5 (2.0–6.5) | 3.0 (2.0–5.0) | 1.5 (1.0–3.0) | 2.0 (2.0–4.0) | 3.0 (2.0–3.0) | 3.0 (2.0–4.0) |
| MAA based on negative trials | |||||||
| All trials negative | 3 (15.0%) | 1 (12.5%) | 2 (16.7%) | 2 (12.5%) | 3 (17.6%) | 2 (5.4%) | 13 (11.8%) |
| Negative trials, at least one positive | 1 (5.0%) | 0 (0.0%) | 2 (16.7%) | 1 (6.3%) | 0 (0.0%) | 2 (5.4%) | 6 (5.5%) |
| No negative trials | 16 (80.0%) | 7 (87.5%) | 8 (66.7%) | 13 (81.3%) | 14 (82.4%) | 33 (89.2%) | 91 (82.7%) |
| No of trials | n = 27 | n = 13 | n = 27 | n = 26 | n = 21 | n = 45 | n = 159 |
| Fulfilment of main study objective | |||||||
| Main end-point met | 23 (85.2%) | 11 (84.6%) | 21 (77.8%) | 23 (88.5%) | 18 (85.7%) | 40 (88.9%) | 136 (85.5%) |
| Not fulfilling objective | 4 (14.8%) | 2 (15.4%) | 5 (18.5%) | 2 (7.7%) | 2 (9.5%) | 5 (11.1%) | 20 (12.6%) |
| Unknown | 0 (0.0%) | 0 (0.0%) | 1 (3.7%) | 1 (3.8%) | 1 (4.8%) | 0 (0.0%) | 3 (1.9%) |
| Conclusion of trial based on subgroupsa | 5 (18.5%) | 0 (0.0%) | 1 (3.7%) | 8 (30.8%) | 2 (9.5%) | 4 (8.9%) | 20 (12.6%) |
| Blinding | |||||||
| Double blind | 8 (29.6%) | 12 (92.3%) | 12 (44.4%) | 7 (26.9%) | 15 (71.4%) | 26 (57.8%) | 80 (50.3%) |
| Single blind | 1 (3.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (2.2%) | 2 (1.3%) |
| Open label | 18 (66.7%) | 1 (7.7%) | 13 (48.1%) | 19 (73.1%) | 6 (28.6%) | 18 (40.0%) | 75 (47.2%) |
| NA | 0 (0.0%) | 0 (0.0%) | 2 (7.4%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 2 (1.3%) |
| Randomisation and controls | |||||||
| Randomized | 14 (51.9%) | 13 (100.0%) | 17 (63.0%) | 10 (38.5%) | 18 (85.7%) | 37 (82.2%) | 109 (68.6%) |
| Placebo controlled | 7 (25.9%) | 12 (92.3%) | 12 (44.4%) | 5 (19.2%) | 14 (66.7%) | 25 (55.6%) | 75 (47.2%) |
| Active controlled | 3 (11.1%) | 1 (7.7%) | 4 (14.8%) | 3 (11.5%) | 2 (9.5%) | 8 (17.8%) | 21 (13.2%) |
| Not controlled | 12 (44.4%) | 0 (0.0%) | 11 (40.7%) | 17 (65.4%) | 4 (19.0%) | 9 (20.0%) | 53 (33.3%) |
| Other | 5 (18.5%) | 0 (0.0%) | 0 (0.0%) | 1 (3.8%) | 1 (4.8%) | 3 (6.7%) | 10 (6.3%) |
| No. of Arms | |||||||
| 1 arm | 12 (44.4%) | 0 (0.0%) | 8 (29.6%) | 16 (61.5%) | 3 (14.3%) | 8 (17.8%) | 47 (29.6%) |
| 2 arms | 14 (51.9%) | 11 (84.6%) | 14 (51.9%) | 9 (34.6%) | 16 (76.2%) | 20 (44.4%) | 84 (52.8%) |
| 3 arms | 1 (3.7%) | 0 (0.0%) | 4 (14.8%) | 1 (3.8%) | 2 (9.5%) | 14 (31.1%) | 22 (13.8%) |
| 4 arms | 0 (0.0%) | 2 (15.4%) | 1 (3.7%) | 0 (0.0%) | 0 (0.0%) | 3 (6.7%) | 6 (3.8%) |
| General design | |||||||
| Parallel groups | 14 (51.9%) | 11 (84.6%) | 17 (63.0%) | 10 (38.5%) | 17 (81.0%) | 37 (82.2%) | 106 (66.7%) |
| Single arm | 12 (44.4%) | 0 (0.0%) | 8 (29.6%) | 16 (61.5%) | 3 (14.3%) | 8 (17.8%) | 47 (29.6%) |
| Crossover | 0 (0.0%) | 0 (0.0%) | 2 (7.4%) | 0 (0.0%) | 1 (4.8%) | 0 (0.0%) | 3 (1.9%) |
| Randomised withdrawal | 0 (0.0%) | 2 (15.4%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 2 (1.3%) |
| Historical control | 1 (3.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (0.6%) |
| Outcomes | |||||||
| Final variable | 12 (44.4%) | 11 (84.6%) | 3 (11.1%) | 1 (3.8%) | 4 (19.0%) | 9 (20.0%) | 40 (25.2%) |
| Intermediate variable | 15 (55.6%) | 2 (15.4%) | 24 (88.9%) | 25 (96.2%) | 17 (81.0%) | 36 (80.0%) | 119 (74.8%) |
| Single variable | 21 (77.8%) | 11 (84.6%) | 21 (77.8%) | 21 (80.8%) | 17 (81.0%) | 31 (68.9%) | 122 (76.7%) |
| Composite variable | 1 (3.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (4.8%) | 13 (28.9%) | 15 (9.4%) |
| Co-primary variables | 2 (7.4%) | 2 (15.4%) | 2 (7.4%) | 4 (15.4%) | 2 (9.5%) | 1 (2.2%) | 13 (8.2%) |
| Multiple end-points | 3 (11.1%) | 0 (0.0%) | 4 (14.8%) | 1 (3.8%) | 1 (4.8%) | 0 (0.0%) | 9 (5.7%) |
| Type of variables for main outcome | |||||||
| Continuous | 0 (0.0%) | 8 (61.5%) | 11 (40.7%) | 5 (19.2%) | 13 (61.9%) | 13 (28.9%) | 50 (31.4%) |
| Discrete | 20 (74.1%) | 3 (23.1%) | 13 (48.1%) | 18 (69.2%) | 6 (28.6%) | 11 (24.4%) | 71 (44.7%) |
| Continuous and discrete | 1 (3.7%) | 1 (7.7%) | 3 (11.1%) | 2 (7.7%) | 1 (4.8%) | 0 (0.0%) | 8 (5.0%) |
| Time to event | 6 (22.2%) | 1 (7.7%) | 0 (0.0%) | 1 (3.8%) | 1 (4.8%) | 21 (46.7%) | 30 (18.9%) |
| Includes biomarkers | 18 (66.7%) | 3 (23.1%) | 22 (81.5%) | 24 (92.3%) | 15 (71.4%) | 28 (62.2%) | 110 (69.2%) |
| Type of objective | |||||||
| Superiority | 13 (48.1%) | 12 (92.3%) | 14 (51.9%) | 8 (30.8%) | 16 (76.2%) | 36 (80.0%) | 99 (62.3%) |
| Value estimation | 12 (44.4%) | 0 (0.0%) | 11 (40.7%) | 18 (69.2%) | 3 (14.3%) | 9 (20.0%) | 53 (33.3%) |
| Non-inferiority | 1 (3.7%) | 1 (7.7%) | 1 (3.7%) | 0 (0.0%) | 2 (9.5%) | 0 (0.0%) | 5 (3.1%) |
| NA | 1 (3.7%) | 0 (0.0%) | 1 (3.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 2 (1.3%) |
| Extent of exposure for safety assessment from pivotal trials | n = 20 | n = 8 | n = 12 | n = 16 | n = 17 | n = 37 | n = 110 |
| Population randomized | |||||||
| Mean (SD) | 223.1 (177.0) | 226.9 (213.3) | 362.8 (408.9) | 312.3 (289.0) | 78.6 (57.9) | 394.6 (260.5) | 286.9 (268.5) |
| Median (P25-P75) | 132.5 (95.5–386.5) | 165.0 (56.0–343.5) | 167.5 (120.0–571.0) | 185.0 (90.5–543.5) | 45.0 (39.0–118.0) | 358.0 (203.0–602.0) | 172.0 (87.0–447.0) |
| {min,Max} | {36.0–600.0} | {31.0–655.0} | {27.0–1485.0} | {12.0–1027.0} | {28.0–219.0} | {7.0–1020.0} | {7.0–1485.0} |
| Population on experimental treatment | |||||||
| Mean (SD) | 140.7 (110.9) | 130.6 (124.0) | 277.3 (394.3) | 263.2 (272.8) | 48.8 (31.7) | 233.9 (133.9) | 189.8 (203.0) |
| Median (P25-P75) | 93.0 (64.0–193.0) | 101.0 (28.5–197.0) | 140.0 (97.0–301.5) | 172.0 (45.5–416.5) | 39.0 (22.0–65.0) | 208.0 (125.0–318.0) | 121.0 (62.0–286.0) |
| {min,Max} | {36.0–449.0} | {15.0–377.0} | {27.0–1485.0} | {12.0–1027.0} | {17.0–117.0} | {7.0–568.0} | {7.0–1485.0} |
| Safety set | |||||||
| Mean (SD) | 140.4 (110.3) | 144.4 (127.1) | 272.3 (396.5) | 274.6 (270.5) | 48.7 (31.6) | 229.9 (131.7) | 190.5 (202.5) |
| Median (P25-P75) | 92.0 (64.0–190.0) | 115.5 (34.5–239.0) | 138.5 (73.5–298.5) | 202.5 (44.5–421.0) | 39.0 (22.0–65.0) | 207.0 (124.0–300.0) | 120.5 (62.0–293.0) |
| {min,Max} | {36.0–449.0} | {23.0–354.0} | {27.0–1485.0} | {12.0–1027.0} | {17.0–117.0} | {7.0–563.0} | {7.0–1485.0} |
| Rare or very rare conditionsb | n = 19 | n = 6 | n = 11 | n = 15 | n = 12 | n = 37 | n = 100 |
| Population randomized | |||||||
| Mean (SD) | 230.6 (178.5) | 289.5 (211.7) | 393.3 (414.3) | 323.3 (295.6) | 88.1 (65.8) | 394.6 (260.5) | 309.5 (271.3) |
| Median (P25-P75) | 134.0 (104.0–415.0) | 251.5 (139.0–375.0) | 170.0 (125.0–586.0) | 196.0 (88.0–559.0) | 61.0 (32.0–131.0) | 358.0 (203.0–602.0) | 205.5 (108.0–452.0) |
| {min,Max} | {36.0–600.0} | {65.0–655.0} | {64.0–1485.0} | {12.0–1027.0} | {28.0–219.0} | {7.0–1020.0} | {7.0–1485.0} |
| Population on experimental treatment | |||||||
| Mean (SD) | 143.8 (113.0) | 167.8 (122.0) | 300.0 (405.2) | 270.9 (280.6) | 56.2 (33.7) | 233.9 (133.9) | 204.3 (207.1) |
| Median (P25-P75) | 102.0 (63.0–207.0) | 153.5 (74.0–215.0) | 165.0 (111.0–306.0) | 196.0 (43.0–449.0) | 48.0 (28.0–77.0) | 208.0 (125.0–318.0) | 143.0 (69.5–298.5) |
| {min,Max} | {36.0–449.0} | {34.0–377.0} | {64.0–1485.0} | {12.0–1027.0} | {17.0–117.0} | {7.0–568.0} | {7.0–1485.0} |
| Safety set | |||||||
| Mean (SD) | 143.5 (112.4) | 182.8 (124.5) | 294.6 (407.8) | 283.1 (277.7) | 56.1 (33.5) | 229.9 (131.7) | 204.9 (206.7) |
| Median (P25-P75) | 100.0 (63.0–201.0) | 168.0 (74.0–299.0) | 162.0 (83.0–301.0) | 257.0 (43.0–447.0) | 48.0 (28.0–77.0) | 207.0 (124.0–300.0) | 151.0 (65.0–297.5) |
| {min,Max} | {36.0–449.0} | {34.0–354.0} | {62.0–1485.0} | {12.0–1027.0} | {17.0–117.0} | {7.0–563.0} | {7.0–1485.0} |
| Ultrarare conditionsb | n = 1 | n = 2 | n = 1 | n = 1 | n = 5 | n = 0 | n = 10 |
| Population randomized | |||||||
| Mean (SD) | 80.0 (−) | 39.0 (11.3) | 27 (−) | 147.0 (−) | 55.8 (23.7) | 61.1 (37.1) | |
| Median (P25-P75) | 39.0 (31.0–47.0) | 45.0 (41.0–58.0) | 46.0 (39.0–80.0) | ||||
| {min,Max} | {31.0–47.0} | {39.0–96.0} | {27.0–147.0} | ||||
| Population on experimental treatment | |||||||
| Mean (SD) | 80.0 (−) | 19.0 (5.7) | 27 (−) | 147.0 (−) | 31.0 (18.8) | 44.7 (41.8) | |
| Median (P25-P75) | 19.0 (15.0–23.0) | 22.0 (21.0–29.0) | 25.0 (21.0–64.0) | ||||
| {min,Max} | {15.0–23.0} | {19.0–64.0} | {15.0–147.0} | ||||
| Safety set | |||||||
| Mean (SD) | 80.0 (−) | 29.0 (8.5) | 27 (−) | 147.0 (−) | 31.0 (18.8) | 46.7 (40.7) | |
| Median (P25-P75) | 29.0 (23.0–35.0) | 22.0 (21.0–29.0) | 28.0 (22.0–64.0) | ||||
| {min,Max} | {23.0–35.0} | {19.0–64.0} | {19.0–147.0} | ||||
aConclusion of trial based on subgroups means granting or restriction due to positive or negative effects in subgroups
bRare or very rare conditions: prevalence between ≤5/10,000 and > 1/100,000; Ultrarare: prevalence ≤1/100,000
EPAR European Public Assessment Report, MAA Marketing Authorisation Application, SD Standard Deviation, min minimum, Max Maximum, P25-P75 25th and 75Th percentiles, NA Not Available