Across 131 orphan-designated Phase I EU CTIS trials, the median end-to-end submission-to-authorization time was 53 days with a 46.5-day standard deviation. Country-specific CTIS Part II records had a much longer median recorded span of 350 days with a 285.8-day standard deviation. Faster authorization was associated with June, July and September submissions, adaptive designs, combination treatment and several advanced modalities; the strongest delay signals were December submission, pure Phase I design, paediatric participation and peptide, protein or enzyme modalities.
The cohort median was 53 days. Within 60 days, 72 of 131 trials were authorized (55.0%); 109 of 131 (83.2%) were authorized within 120 days.
The median sits just below 60 days, but the upper tail is material: 48 of 131 trials (36.6%) required at least 90 days and 22 of 131 (16.8%) required more than 120 days.
The median recorded CTIS Part II span was 350 days. Of 376 country Part II records, 113 (30.1%) reached a decision within 60 days, 126 (33.5%) within 90 days and 202 (53.7%) within 365 days.
Austria had the lowest country median at 25 days. Among countries with at least 10 records, France had the lowest median at 289.5 days, followed by Denmark and the Netherlands at 300 days; Greece had the highest at 441 days.
| Country | Records | Median days | SD days |
|---|---|---|---|
| Austria | 5 | 25 | 76.5 |
| Ireland | 4 | 100.5 | 135.5 |
| Norway | 6 | 136.5 | 305.7 |
| Sweden | 8 | 209.5 | 333.5 |
| France | 60 | 289.5 | 288.8 |
| Denmark | 14 | 300 | 322.4 |
| Netherlands | 35 | 300 | 303.3 |
| Portugal | 5 | 326 | 187 |
| Poland | 23 | 351 | 253.2 |
| Belgium | 19 | 352 | 296.3 |
| Germany | 48 | 353 | 292.3 |
| Italy | 60 | 353.5 | 264.3 |
| Slovenia | 2 | 357 | 203 |
| Spain | 62 | 366 | 283.1 |
| Greece | 11 | 441 | 192.2 |
| Czechia | 7 | 468 | 269.8 |
| Hungary | 4 | 621 | 179.1 |
| Finland | 2 | 805 | 41 |
| Romania | 1 | 868 | 0 |
July submissions had the shortest median at 28.5 days, followed by January at 30 days and June and February at 32.5 days. December submissions had a 126-day median and a 75.0% rate of authorization at 90 days or longer.
The strongest seasonal contrast was late-year submission: November and December medians were 102.5 and 126 days, versus 32.5 days in June and 28.5 days in July.
Country count, site count and planned sample size had weak Spearman correlations with EU CTIS end-to-end time. Recruitment window showed the only moderate relationship: longer planned recruitment was associated with shorter authorization time (ρ −0.37, p<0.001).
Scale alone did not explain delay. The pattern was non-linear: trials in 2 to 3 countries had a 103.5-day median, while trials in 4 to 6 countries had a 47-day median; site count itself was essentially uncorrelated with timing.
Adaptive trials had a 49-day median versus 82.5 days for nonadaptive trials. Combination trials had a 49.5-day median and 28.9% rate of 90-day delay, compared with 74 days and 47.3% for single-treatment trials.
The clearest delay profiles were pure Phase I trials at a 106.5-day median and 58.3% 90-day delay rate, and paediatric trials at 70 days and 46.9%, compared with 50 days and 30.5% for nonpaediatric trials.
Gene therapy had a 35-day median, while cell therapy and monoclonal antibody trials each had a 42-day median. Peptide, protein or enzyme trials had a 114-day median and 61.5% rate of 90-day delay. Immunology trials also had a 114-day median and 66.7% 90-day delay rate.
Modality and clinical context were stronger discriminators than simple trial scale. The largest repeated disease cluster, multiple myeloma, had a 35-day median across 10 trials and only 1 of 10 trials reached 90 days or longer.
For an EU Phase I rare-disease CTIS submission, 60 days is a realistic median-centered planning anchor, but programmes submitted late in the calendar year or involving paediatric, pure Phase I or complex protein-based modalities should carry a 90-to-120-day end-to-end contingency.