Across 59 Phase I infectious disease trials submitted through the EU Clinical Trials Information System (CTIS), the median end to end review was 73 days with a 40.8 day standard deviation. Country specific CTIS Part II decisions had a similar 70 day median but a far wider 234.8 day standard deviation, driven by large country and site footprint differences. Multicountry trials, five or more sites, respiratory infections, viral hepatitis, adaptive designs, and CRO supported programs were the clearest observed delay signals.
End to end timing measures the initial EU CTIS submission to the first CTIS authorization for the trial. The distribution ranged from 7 to 170 days. A total of 34 of 59 trials (57.6%) took at least 60 days and 25 of 59 (42.4%) took at least 90 days.
A 60 day planning assumption covered only 42.4% of EU submissions. A 120 day allowance covered 52 of 59 trials (88.1%), making four months a materially more reliable operating benchmark than two months.
CTIS Part II is country specific and covers national and local requirements. Across 71 country decisions, 33 (46.5%) were completed within 60 days, 37 (52.1%) within 90 days, and 57 (80.3%) within 365 days. End to end review is a trial level metric and is therefore not attributed to individual countries.
The similar 70 day median conceals much greater country variability: the 234.8 day SD was nearly six times the 40.8 day end to end SD. Country selection and national site footprint therefore drive schedule risk beyond the central EU CTIS review.
Ireland had the lowest observed median at 14 days but only one decision. Among countries with at least three decisions, the Netherlands had the lowest median at 15 days, followed by Poland at 31 and Romania at 33. Germany had the highest median at 355 days, followed by Austria at 335 and Czechia at 211.
| Country | n | Median | SD |
|---|---|---|---|
| Ireland | 1 | 14 | — |
| Netherlands | 10 | 15 | 186.3 |
| Poland | 3 | 31 | 26.7 |
| Romania | 3 | 33 | 2.1 |
| Portugal | 1 | 54 | — |
| Bulgaria | 4 | 63 | 102 |
| Italy | 2 | 65.5 | 2.1 |
| Spain | 10 | 92.5 | 331.6 |
| France | 7 | 119 | 278.3 |
| Sweden | 1 | 122 | — |
| Denmark | 6 | 126.5 | 194.1 |
| Belgium | 10 | 184 | 151.7 |
| Czechia | 1 | 211 | — |
| Austria | 2 | 335 | 441.2 |
| Germany | 10 | 355 | 304.8 |
The number of participating countries correlated with longer end to end review (Spearman ρ=0.34, p=0.008), as did total sites (ρ=0.36, p=0.005). Multicountry trials had a 112.5 day median versus 62 days for single country trials. Trials with five or more sites had a 111 day median versus 53.5 days for one site.
Country and site count were more informative than enrollment scale. Target sample size showed virtually no correlation with end to end review (ρ≈0.00, p=0.975), and total participants also showed little association (ρ=−0.10, p=0.444).
Country level site count correlated with Part II time (ρ=0.30, p=0.010). One site country submissions had a 58.5 day median, compared with 70 days for two to four sites and 386.5 days for five or more sites. Seven of eight country submissions with five or more sites (87.5%) took at least 90 days.
National site expansion was the clearest Part II planning risk. Where speed is critical, sequencing a smaller initial site package before adding sites may reduce exposure to the extreme delay tail.
Vaccine trials had a 53 day median and 25.0% reached 90 days or longer. Cell therapy and other modalities had medians of 108 and 110 days, with 75.0% and 83.3% reaching 90 days. By disease, HIV and bacterial infection trials had medians of 51 and 55.5 days, while viral hepatitis and respiratory infection trials reached 94 and 102 days.
The modality and disease signals align with operational complexity: cell therapy, mixed or novel modalities, respiratory programs, and hepatitis programs more often carried broader review packages or footprints. Vaccine status alone was not a delay risk in this cohort.
Adaptive trials had a 103 day median versus 69 days for nonadaptive trials. Trials with a CRO had a 106 day median versus 71 days without one, and first in human programs had a 110 day median versus 72 days. These associations were weaker than the site and country effects and appear to function mainly as markers of program complexity.
Complex design labels should trigger earlier CTIS readiness work, but they should not be treated as independent causes. Combination treatment was not a consistent delay signal: its median was 51.5 days versus 79 days for noncombination trials, while ≥90 day rates were almost identical at 41.7% and 42.6%.
Among months with at least four submissions, July had the shortest median at 31 days and November followed at 45 days. December had the longest median at 116 days and an 83.3% rate of 90 day or longer reviews; August reached 106.5 days and 75.0%. No year variable was used in this analysis.
Where program timing is flexible, late summer and year end EU submissions warrant additional schedule buffer. The month signal is best used as a planning overlay after accounting for countries and sites, which showed the stronger quantitative relationships.
The evidence points to an operational rather than enrollment driven model of CTIS delay. The highest value planning actions are to control the initial country and site footprint, prebuild country Part II packages for slower markets, and add schedule buffer for complex modalities and calendar periods associated with delay.
For Phase I infectious disease EU submissions, the most actionable route to shorter CTIS timelines is not reducing target enrollment. It is limiting the initial country and site footprint, selecting Part II countries based on both median and variability, and treating multicountry, high site count, respiratory, hepatitis, adaptive, and first in human programs as high buffer submissions.