Across 238 unique European CTIS infectious disease Phase II and Phase III trials, safety and adverse event endpoints were the most common endpoint family, appearing in 150 trials, or 63.0%. Primary endpoints were more balanced, led by safety in 44 trials, virologic load or suppression in 42 trials, and clinical response or symptom recovery in 39 trials. Secondary endpoints were much more safety-heavy, with safety endpoints used in 118 trials, or 49.6%.
Endpoint families were normalized at trial level, meaning each trial counts once per endpoint family even if it listed multiple related measures. Safety and adverse events appeared in 150 of 238 trials, or 63.0%, followed by biomarker or cellular immune markers in 99 trials, or 41.6%.
The infectious disease endpoint stack is broad, but safety is the common denominator. Efficacy families are more disease-dependent: virologic endpoints cluster in HIV and hepatitis, immunogenicity in vaccines, and mortality or hospitalization in bacterial sepsis and severe respiratory infection trials.
Primary endpoints were present as classified endpoint families in 178 of 238 trials, while secondary endpoint families appeared in 191 of 238 trials. Exploratory-labelled endpoint families were rare, appearing in 10 of 238 trials, or 4.2%.
| Role | Most frequent endpoint family | Trials | Share |
|---|---|---|---|
| Primary | Safety / adverse events | 44 / 238 | 18.5% |
| Primary | Virologic load / clearance / suppression | 42 / 238 | 17.6% |
| Primary | Clinical response / cure / symptom recovery | 39 / 238 | 16.4% |
| Secondary | Safety / adverse events | 118 / 238 | 49.6% |
| Secondary | Biomarker / cellular immune markers | 83 / 238 | 34.9% |
| Secondary | Microbiological / pathogen response | 72 / 238 | 30.3% |
| Exploratory | Clinical response / cure / symptom recovery | 5 / 238 | 2.1% |
| Exploratory | Biomarker / cellular immune markers | 5 / 238 | 2.1% |
| Exploratory | Microbiological / pathogen response | 4 / 238 | 1.7% |
Primary endpoints are not dominated by one single infectious disease convention: safety, virologic response, clinical response, and incidence/prevention all appear in at least 34 trials. Secondary endpoints are more standardized around safety follow-up and supportive biological or microbiological measures.
The dataset included 96 Phase II trials, 129 Phase III trials, and 13 combined Phase II/III trials. Safety appeared in 66 of 96 Phase II trials, 73 of 129 Phase III trials, and 11 of 13 combined Phase II/III trials.
Phase II infectious disease trials are more mechanistic and dose-confirming, with biomarker/cellular endpoints in 53.1% and PK/PD endpoints in 33.3%. Phase III trials move toward patient-relevant and regulator-facing outcomes, including incidence/prevention, clinical response, mortality, and hospitalization.
Among disease groups with at least 15 trials, HIV, bacterial/sepsis/UTI, vaccine-preventable or opportunistic viral infections, severe pulmonary infections, COVID-19, viral hepatitis, and respiratory viral infections each showed a distinct endpoint signature.
| Disease group | Trials | Dominant endpoint families |
|---|---|---|
| HIV | 40 | Safety 33 / 40, 82.5%; biomarker/cellular 32 / 40, 80.0%; virologic 27 / 40, 67.5% |
| Bacterial / sepsis / UTI | 45 | Hospitalization 24 / 45, 53.3%; mortality 24 / 45, 53.3%; safety 23 / 45, 51.1% |
| Vaccine-preventable / opportunistic viral | 27 | Safety 19 / 27, 70.4%; immunogenicity 9 / 27, 33.3%; incidence/prevention 9 / 27, 33.3% |
| Pulmonary / severe respiratory infections | 23 | Safety 16 / 23, 69.6%; microbiological 16 / 23, 69.6%; clinical response 14 / 23, 60.9% |
| COVID-19 / post-COVID | 21 | Clinical response 15 / 21, 71.4%; PRO/QoL 11 / 21, 52.4%; safety 11 / 21, 52.4% |
| Viral hepatitis | 17 | Virologic 16 / 17, 94.1%; safety 14 / 17, 82.4%; incidence/prevention 11 / 17, 64.7% |
| Respiratory viral infections | 15 | Safety 12 / 15, 80.0%; immunogenicity 11 / 15, 73.3%; mortality 8 / 15, 53.3% |
HIV and hepatitis trials are virology-heavy, vaccine and respiratory viral trials are immunogenicity-heavy, and bacterial/sepsis trials are outcome-heavy. This means endpoint benchmarking for CTIS submissions should be disease-specific rather than based on one broad infectious disease standard.
The largest sub-disease clusters were HIV/HIV-1 infection with 37 trials, COVID-19/SARS-CoV-2/long COVID with 21 trials, sepsis with 14 trials, UTI/pyelonephritis/complicated UTI with 13 trials, CMV infection with 11 trials, and hepatitis D/HDV infection with 11 trials.
Sub-disease-level benchmarking is most reliable for HIV, COVID-19, sepsis, UTI, CMV, HDV, and RSV. Examples include HIV endpoints led by safety in 30 of 37 trials and virologic endpoints in 25 of 37 trials; HDV endpoints led by virologic measures in 10 of 11 trials; and RSV endpoints led by immunogenicity in 8 of 10 trials.
Four modality groups had at least 10 trials: small molecules, vaccine/RNA vaccine products, antibody/biologic products, and protein/enzyme therapies. Small molecules accounted for 151 trials, while vaccine/RNA vaccine products accounted for 40 trials.
| Modality | Trials | Endpoint profile |
|---|---|---|
| Small molecule | 151 | Safety 96 / 151, 63.6%; microbiological 67 / 151, 44.4%; biomarker/cellular 66 / 151, 43.7% |
| Vaccine/RNA vaccine | 40 | Safety 30 / 40, 75.0%; immunogenicity 29 / 40, 72.5%; hospitalization 13 / 40, 32.5% |
| Antibody/biologic | 12 | Incidence/prevention 9 / 12, 75.0%; safety 9 / 12, 75.0%; virologic 8 / 12, 66.7% |
| Protein/enzyme | 11 | Safety 9 / 11, 81.8%; biomarker/cellular 7 / 11, 63.6%; incidence/prevention 5 / 11, 45.5% |
Vaccine/RNA vaccine trials are the clearest modality-specific endpoint group, with immunogenicity endpoints in 72.5% of trials. Small molecule trials are broader and more infection-treatment oriented, combining safety, microbiology, biomarkers, and clinical response.
All 238 included trials had initial CTIS submission and first CTIS authorization dates. The median time from initial CTIS submission to first authorization was 93 days, with an observed range of 1 to 217 days.
For EU infectious disease trial planning, the endpoint package can be paired with CTIS timing expectations. The 93-day median gives a practical submission-to-first-authorization benchmark, while microbiological endpoint trials showed a shorter median of 85 days in this dataset.
The same endpoint and CTIS context supports additional operational and design questions beyond simple endpoint frequency.
The dataset can support practical design checks before EU submission: whether a protocol has the expected disease-specific efficacy family, whether safety is sufficiently represented, whether PRO/QoL is relevant for the indication, and whether economic or implementation endpoints are common enough to justify inclusion.
Endpoint families were normalized to comparable analytical groups. AE means adverse event; SAE means serious adverse event; PK/PD means pharmacokinetics/pharmacodynamics; PRO/QoL means patient-reported outcome or quality of life; CTIS means the EU Clinical Trials Information System.
For protocol or CTIS submission benchmarking, the most useful comparator is not the overall infectious disease average alone. The stronger benchmark is the disease-by-modality combination: HIV and hepatitis should be checked against virologic/biomarker norms, vaccines against immunogenicity/safety norms, and severe bacterial or pulmonary infection trials against clinical, microbiological, mortality, and healthcare-use norms.