Across 237 Phase II rare disease trials, the median EU CTIS end to end review was 104 days with an SD of 45.0 days. Only 76 of 237 trials (32.1%) reached first authorization within 60 days and 98 of 237 (41.4%) within 90 days. The recorded country specific CTIS Part II median was 245.5 days with an SD of 246.6 days, while smaller single country and low site submissions moved fastest.
The end to end timeline runs from the initial EU CTIS submission to the first CTIS authorization. The median was 104 days, the mean was 85.8 days, and the interquartile range was 38 to 116 days.
EU CTIS authorization was concentrated around the three to four month window: 93 of 237 trials (39.2%) finished between 91 and 120 days. The distribution was bounded at the upper end, with only 3 trials (1.3%) exceeding 180 days.
CTIS Part II is country specific and is reported separately from the overall EU submission timeline. Across 804 country level records, the recorded median was 245.5 days and SD was 246.6 days.
| Country | Records | Median days | SD days | Within 60 | Within 90 |
|---|---|---|---|---|---|
| Estonia | 1 | 16.0 | — | 100.0% | 100.0% |
| Latvia | 1 | 20.0 | — | 100.0% | 100.0% |
| Lithuania | 1 | 30.0 | — | 100.0% | 100.0% |
| Ireland | 11 | 39.0 | 261.4 | 63.6% | 63.6% |
| Finland | 4 | 41.0 | 212.3 | 75.0% | 75.0% |
| Croatia | 2 | 82.5 | 17.7 | 0.0% | 50.0% |
| Romania | 8 | 89.5 | 246.1 | 37.5% | 50.0% |
| Slovenia | 2 | 91.0 | 89.1 | 50.0% | 50.0% |
| Norway | 18 | 115.0 | 266.3 | 38.9% | 44.4% |
| Sweden | 22 | 128.5 | 253.9 | 31.8% | 45.5% |
| Bulgaria | 8 | 133.0 | 146.9 | 25.0% | 50.0% |
| Netherlands | 68 | 203.0 | 265.9 | 38.2% | 39.7% |
| Poland | 50 | 214.5 | 224.4 | 40.0% | 42.0% |
| Germany | 101 | 233.0 | 249.2 | 31.7% | 36.6% |
| Portugal | 15 | 237.0 | 207.8 | 33.3% | 40.0% |
| Belgium | 45 | 261.0 | 252.9 | 35.6% | 35.6% |
| France | 112 | 263.5 | 251.6 | 30.4% | 34.8% |
| Spain | 124 | 265.0 | 251.6 | 29.0% | 36.3% |
| Czechia | 23 | 269.0 | 242.5 | 26.1% | 34.8% |
| Italy | 116 | 270.0 | 240.6 | 26.7% | 31.0% |
| Slovakia | 2 | 276.5 | 344.4 | 50.0% | 50.0% |
| Greece | 20 | 325.5 | 219.3 | 20.0% | 25.0% |
| Austria | 16 | 349.5 | 217.5 | 25.0% | 25.0% |
| Denmark | 20 | 398.0 | 284.6 | 45.0% | 45.0% |
| Hungary | 14 | 405.0 | 278.8 | 28.6% | 28.6% |
Among countries with at least eight records, Ireland had the lowest median at 39.0 days (n=11), followed by Romania at 89.5 days (n=8) and Norway at 115.0 days (n=18). The highest medians were Hungary at 405.0 days (n=14) and Denmark at 398.0 days (n=20); wide SDs show substantial within country dispersion.
Submission month was associated with materially different end to end CTIS timelines even without using year as an analytical variable. September submissions had the shortest median at 51.0 days, while November and December had medians of 127.0 and 123.0 days.
| Month | Trials | Median days | Below median | 60 days or more | 90 days or more |
|---|---|---|---|---|---|
| January | 13 | 94.0 | 61.5% | 69.2% | 61.5% |
| February | 18 | 91.5 | 50.0% | 72.2% | 50.0% |
| March | 16 | 109.0 | 43.8% | 87.5% | 68.8% |
| April | 22 | 90.5 | 59.1% | 63.6% | 50.0% |
| May | 17 | 95.0 | 52.9% | 52.9% | 52.9% |
| June | 18 | 103.0 | 50.0% | 61.1% | 55.6% |
| July | 26 | 101.5 | 53.8% | 65.4% | 65.4% |
| August | 23 | 108.0 | 43.5% | 73.9% | 69.6% |
| September | 25 | 51.0 | 76.0% | 44.0% | 36.0% |
| October | 22 | 122.0 | 36.4% | 72.7% | 68.2% |
| November | 13 | 127.0 | 30.8% | 92.3% | 76.9% |
| December | 24 | 123.0 | 33.3% | 79.2% | 70.8% |
September was the strongest timing window: 19 of 25 submissions (76.0%) finished below the 104 day median and only 9 of 25 (36.0%) reached 90 days or more. November was the clearest delay month, with 12 of 13 (92.3%) lasting at least 60 days and 10 of 13 (76.9%) at least 90 days.
Smaller EU submissions were consistently faster. Single country trials had a median of 85.0 days, compared with 112.0 days for trials spanning four to five countries. Trials with one to five sites had a median of 85.5 days, versus 109.0 days above 20 sites.
| Submission footprint | Trials | Median days | Below median | 60 days or more | 90 days or more |
|---|---|---|---|---|---|
| 1 country | 85 | 85.0 | 64.7% | 63.5% | 49.4% |
| 2 to 3 countries | 47 | 100.0 | 51.1% | 63.8% | 59.6% |
| 4 to 5 countries | 49 | 112.0 | 30.6% | 81.6% | 75.5% |
| 6 or more countries | 56 | 108.5 | 42.9% | 67.9% | 62.5% |
| 1 to 5 sites | 96 | 85.5 | 61.5% | 60.4% | 49.0% |
| 6 to 10 sites | 43 | 109.0 | 37.2% | 81.4% | 69.8% |
| 11 to 20 sites | 50 | 103.0 | 50.0% | 64.0% | 60.0% |
| More than 20 sites | 47 | 109.0 | 38.3% | 76.6% | 72.3% |
The clearest operational advantage was a compact footprint: 55 of 85 single country trials (64.7%) finished below the median, compared with 15 of 49 four to five country trials (30.6%). Likewise, 47 of 96 trials with one to five sites (49.0%) reached 90 days or more versus 34 of 47 trials above 20 sites (72.3%).
Comparator status produced the largest design separation. Trials without a comparator had a median of 82.0 days, versus 108.5 days when a comparator was present. Combination studies were faster than single treatment studies at 86.0 versus 108.0 days.
| Feature | Trials | Median days | Below median | 60 days or more | 90 days or more |
|---|---|---|---|---|---|
| Comparator absent | 121 | 82.0 | 57.0% | 57.9% | 47.9% |
| Comparator present | 116 | 108.5 | 42.2% | 79.3% | 72.4% |
| Nonrandomized | 131 | 91.0 | 54.2% | 61.1% | 51.1% |
| Randomized | 106 | 108.0 | 44.3% | 77.4% | 70.8% |
| No digital recruitment | 185 | 98.0 | 54.1% | 63.2% | 55.1% |
| Digital recruitment used | 52 | 111.0 | 34.6% | 86.5% | 76.9% |
| Combination treatment | 64 | 86.0 | 62.5% | 54.7% | 50.0% |
| Single treatment | 173 | 108.0 | 45.1% | 73.4% | 63.6% |
| Paediatric trial | 95 | 92.0 | 56.8% | 64.2% | 52.6% |
| Adult only trial | 142 | 108.0 | 45.1% | 71.1% | 64.8% |
| Orphan designated | 113 | 96.0 | 54.0% | 63.7% | 54.0% |
| Not orphan designated | 124 | 105.0 | 46.0% | 72.6% | 65.3% |
Comparator present trials had 84 of 116 (72.4%) at 90 days or more, compared with 58 of 121 (47.9%) without a comparator. Digital recruitment was also a marker of more complex submissions: 40 of 52 (76.9%) reached 90 days or more versus 102 of 185 (55.1%) without it. These are associations, not evidence that the feature itself caused delay.
Across recurring modalities, gene or RNA therapy had a median of 92.0 days, antibody based therapy 99.0 days, and protein or enzyme therapy 109.5 days. Disease level comparisons were more concentrated because most rare diseases appeared only once or twice.
| Modality | Trials | Median days | Below median | 90 days or more |
|---|---|---|---|---|
| Gene or RNA therapy | 23 | 92.0 | 52.2% | 56.5% |
| Oligonucleotide | 18 | 96.5 | 55.6% | 61.1% |
| Antibody based | 54 | 99.0 | 55.6% | 57.4% |
| Cell therapy | 14 | 104.0 | 50.0% | 57.1% |
| Small molecule | 83 | 104.0 | 48.2% | 60.2% |
| Protein or enzyme | 36 | 109.5 | 38.9% | 66.7% |
| Disease | Trials | Median days | Below median | 90 days or more |
|---|---|---|---|---|
| Multiple myeloma | 7 | 35.0 | 71.4% | 28.6% |
| Amyotrophic lateral sclerosis | 5 | 127.0 | 0.0% | 100.0% |
Protein or enzyme trials showed the highest modality level delay rate, with 24 of 36 (66.7%) at 90 days or more. Among recurrent diseases, multiple myeloma had a 35.0 day median (n=7), while amyotrophic lateral sclerosis had a 127.0 day median and 5 of 5 trials at 90 days or more.
Overall, 162 of 237 trials (68.4%) lasted at least 60 days and 142 of 237 (59.9%) lasted at least 90 days. The highest descriptive delay rates clustered around late calendar submissions and more operationally complex designs.
| Factor | Trials | 60 days or more | 90 days or more | Median days |
|---|---|---|---|---|
| November submission | 13 | 92.3% | 76.9% | 127.0 |
| Digital recruitment used | 52 | 86.5% | 76.9% | 111.0 |
| 4 to 5 countries | 49 | 81.6% | 75.5% | 112.0 |
| Comparator present | 116 | 79.3% | 72.4% | 108.5 |
| Randomized design | 106 | 77.4% | 70.8% | 108.0 |
| More than 20 sites | 47 | 76.6% | 72.3% | 109.0 |
| December submission | 24 | 79.2% | 70.8% | 123.0 |
| Protein or enzyme modality | 36 | 75.0% | 66.7% | 109.5 |
The strongest 90 day delay signals were digital recruitment at 76.9% (40 of 52), November submission at 76.9% (10 of 13), four to five countries at 75.5% (37 of 49), and comparator presence at 72.4% (84 of 116). For planning an EU CTIS submission, footprint and protocol complexity were more consistently associated with delay than sample size alone.
CTIS means the Clinical Trials Information System. End to end is the interval from initial EU CTIS submission to first authorization and is reported only at trial level. Part II is country specific and uses the recorded interval from earliest Part II submission to latest country decision or authorization. SD is standard deviation.