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Table 2 Description of European Public Assessment Reports (EPARs) of orphan medicinal products

From: Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe: methodological uncertainties

  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}
  1. aConclusion of trial based on subgroups means granting or restriction due to positive or negative effects in subgroups
  2. bRare or very rare conditions: prevalence between ≤5/10,000 and > 1/100,000; Ultrarare: prevalence ≤1/100,000
  3. 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