How Long Do Phase II Cardiology CTIS Reviews Take and What Drives Delay?
Across 106 European Phase II cardiology trials, the median CTIS end-to-end review was 91 days (SD 40.3), while 281 country-specific Part II reviews had a median of 99 days (SD 219.6). Scope was the clearest operational signal: trials spanning 4+ countries had a 112-day median and 92.3% reached 90 days or longer, versus 68.5 days and 32.9% for single-country trials.
How long does end-to-end CTIS authorization take?
The trial-level end-to-end median was 91 days across 106 trials, with a mean of 78.8 days, SD 40.3, IQR 37–112, and a range of 2–133 days.
The 90-day point almost exactly split the cohort: 52 of 106 trials were authorized by day 90, while 54 reached 90 days or longer. The distribution then compressed sharply, with 86.8% authorized by day 120.
How long does country-specific CTIS Part II take?
Country-specific Part II reviews had a 99-day median across 281 observations. The SD was 219.6 days and the IQR was 25–349 days, showing a pronounced long tail that is not visible from the median alone.
Part II is more dispersed than the trial-level end-to-end timeline. Although 43.8% of country reviews finished within 60 days, 41.1% lasted at least 180 days and 21.6% lasted at least one year.
Which countries had the shortest and longest Part II timelines?
Among countries with at least five observations, Latvia had the lowest median at 20 days, followed by Denmark at 32 and the Netherlands at 33. Czechia had the highest median at 261.5 days, followed by Hungary at 182.5 and Spain at 165.5.
| Country | n | Median, days | SD, days |
|---|---|---|---|
| Ireland | 1 | 18.0 | — |
| Latvia | 7 | 20.0 | 147.6 |
| Slovenia | 1 | 20.0 | — |
| Denmark | 10 | 32.0 | 240.4 |
| Netherlands | 25 | 33.0 | 192.2 |
| Finland | 2 | 35.0 | 24.0 |
| Poland | 23 | 42.0 | 259.5 |
| Portugal | 6 | 46.0 | 280.9 |
| Austria | 6 | 53.5 | 200.7 |
| Belgium | 18 | 64.5 | 186.1 |
| Norway | 3 | 65.0 | 290.5 |
| Romania | 5 | 85.0 | 242.2 |
| Germany | 36 | 98.5 | 216.7 |
| Italy | 28 | 115.0 | 239.7 |
| Bulgaria | 7 | 118.0 | 198.9 |
| Sweden | 7 | 122.0 | 187.9 |
| France | 28 | 148.5 | 233.1 |
| Spain | 32 | 165.5 | 219.3 |
| Hungary | 10 | 182.5 | 267.3 |
| Greece | 4 | 205.0 | 162.2 |
| Iceland | 1 | 228.0 | — |
| Czechia | 20 | 261.5 | 227.7 |
| Lithuania | 1 | 300.0 | — |
Country medians differed by more than 240 days among countries with at least five observations. Large SDs in several countries indicate mixed fast and very delayed pathways, so the median should be read together with dispersion and sample size.
Does multinational and multisite scope correlate with slower authorization?
Yes. The number of countries correlated with longer end-to-end review (Spearman ρ=0.46), as did total site count (ρ=0.42). These were the strongest continuous operational signals in the dataset.
Single-country trials were 43.5 days faster at the median than trials in 4+ countries. Only 7.7% of 4+ country trials finished below the overall 91-day median, and 92.3% reached at least 90 days.
Does within-country site burden affect Part II?
Country-level site burden showed a smaller but consistent relationship with Part II duration (Spearman ρ=0.27). Median Part II time rose from 45 days for one-site country submissions to 243 days for submissions with eight or more sites.
The 90-day delay rate increased from 36.1% with one site to 68.8% with eight or more sites. Country Part II delay therefore tracked more closely with the number of sites inside that country than with the total number of countries in the trial.
Which sponsor, design and modality factors correlate with delay?
Pharma-sponsored, CRO-supported, adaptive and dose-escalation trials all had longer unadjusted medians. However, CRO-supported trials were also much larger—median 6 countries and 25 sites versus 1 country and 2 sites without a CRO—so several signals reflect program complexity rather than a single causal factor.
| Factor | n | Median days | Below 91d | ≥90d |
|---|---|---|---|---|
| Non-pharma sponsor | 55 | 48.0 | 74.5% | 25.5% |
| Pharma sponsor | 51 | 110.0 | 21.6% | 78.4% |
| No CRO listed | 69 | 68.0 | 65.2% | 34.8% |
| CRO listed | 37 | 109.0 | 18.9% | 81.1% |
| Non-adaptive design | 87 | 83.0 | 54.0% | 46.0% |
| Adaptive design | 19 | 111.0 | 26.3% | 73.7% |
| No dose-escalation flag | 86 | 82.5 | 52.3% | 47.7% |
| Dose-escalation flag | 20 | 97.5 | 35.0% | 65.0% |
The strongest practical distinction was not randomization or blinding. It was whether the submission belonged to a larger, commercially sponsored multinational program. Small-molecule-only trials had a 77-day median, versus 107 days for biologic/protein trials and 109 days for advanced or diagnostic modalities.
Which cardiology disease groups moved fastest or slowest?
Among disease groups with at least five trials, arrhythmia had the longest median at 112 days, followed by pulmonary hypertension at 106 and heart failure/cardiomyopathy at 101.5. Acute cardiac care and surgery was fastest at 68 days.
Disease effects largely tracked operational scope. Pulmonary hypertension trials had a median of 7 countries and 24 sites, while acute cardiac care and surgery trials had 1 country and 3 sites.
Does submission month correlate with review time?
Calendar month showed a descriptive pattern. September submissions had the shortest median at 34 days, followed by July at 68 and October at 72. November was longest at 121.5 days, followed by December at 111.5 and February at 108.
November submissions had an 83.3% rate of reaching at least 90 days, compared with 41.7% in September. Month was analyzed descriptively and should be treated as a planning signal rather than a causal calendar effect.
What factors characterize fast and delayed CTIS pathways?
The data support a practical risk profile for Phase II cardiology EU submissions. Fast pathways were concentrated in narrow-scope, non-pharma or institution-led trials; delayed pathways clustered in multinational, high-site, commercial and complex-modality programs.
Single-country: 67.1% fast; median 68.5 days.
1–3 sites: 66.7% fast; median 72 days.
Non-pharma sponsor: 74.5% fast; median 48 days.
No CRO listed: 65.2% fast; median 68 days.
Small molecule only: 57.1% fast; median 77 days.
4+ countries: 92.3% delayed; median 112 days.
11+ sites: 81.1% delayed; median 111 days.
Pharma sponsor: 78.4% delayed; median 110 days.
CRO listed: 81.1% delayed; median 109 days.
Adaptive design: 73.7% delayed; median 111 days.
For planning, the most defensible early-warning indicators are geographic scope and site burden. Sponsor, CRO, modality and disease signals add context, but much of their apparent effect overlaps with larger multinational trial footprints.
CTIS: Clinical Trials Information System. End-to-end: initial EU CTIS submission to first trial authorization. Part II: country-specific ethical, site and local-document review timeline. SD: standard deviation. Percentages use 106 trial-level observations for end-to-end analyses and 281 country observations for Part II analyses.