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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
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Orphanet Journal of Rare Diseases

ISSN: 1750-1172