Today’s topic is about the lackluster recruitment of US centers in recent CABP trials. We noticed that Eastern European (EE) centers, specifically from Ukraine, Bulgaria, and Serbia, contribute patients in large numbers, actually making these trials feasible.
When sponsors and CROs needed to enroll CABP patients, they could not rely on US centers. Recruitment was abysmally low in the US. Hence, FDA approvals for the CABP indication are predominantly based on data from countries behind the old Iron Curtain.
An article by FDA clinicians and statisticians provides details. Bart et al. analyzed all the latest CABP trials, checking the correlation between the newly introduced ECR and the formerly applied TOC endpoint in trials that were executed according to the latest FDA Guidance [1]. They identified 6 studies of 4 antibacterial drugs; in the paper’s Supplement we find data on regional contributions:
Obviously, there was subpar enrollment at US sites, quite contrary to past CAP studies, at a time when US centers were still major contributors. US patients accounted for only 362/4645 (8%) of all CABP patients in these recent trials. EE countries were star contributors, the US contribution being quite low. Why was there this uneven regional distribution?
FDA usually reviews high-enrolling centers and checks compliance. Hence, there should be no problem with data integrity and protocol adherence in EE countries. As there are no ethnic differences between Eastern European and US patients, these X-US participants are all legitimate CABP cases.
We initially thought that the new FDA Guidance for CABP, introduced in 2014 and finalized in 2020, may be the reason for this dramatic shift away from the US in recruitment dynamics, but we are no longer certain [2],[3].
The only major new element that might impede enrollment in the US is the prior-antibiotic clause which requires <24 hours of non-study antibiotic therapy before entry. In essence, this new rule excludes patients that received more than 1 dose of a longer-acting antibiotic prior to enrollment. This seemingly small (and reasonable!) new criterium should have affected all regions and centers equally. Is there a significant difference in clinical practice that accounts for this imbalance?
Let’s take a look at the top enrolling countries in the Lefamulin trials[4]:
Are EE patients prescribed fewer doses of antibiotics as outpatients prior to hospitalization? Does patient work-up in the US and the pressure to start antibiotics early make patients ineligible? CMS has instituted quality control measures (antibiotic administration not later than 4 hours after triage [5]) which could stand in the way of patient recruitment.
Perhaps we should be asking the other way around: What makes Eastern European centers such star performers, compared to everyone else? What are they doing differently?
No doubt, there is sponsor bias in center and country selection. When CROs select centers for global studies, they are under great pressure to find centers that deliver, preferably with lower per-capita costs. US centers may not be cost competitive, but there is no shortage of CABP patients: Over 5 mio patients seek medical care for CABP each year in the US [6]. However, we cannot explain the regional imbalance.
Is this a negligible and acceptable anomaly, or is it a non-issue? Well, it is the current reality in CABP trials, even if it defies explanation. We’d like to hear from you and get your perspective on this. After all, CABP is a common disease everywhere in the world including the US; the disease is the same, the pathogens are the same, and still there is this regional ‘phenomenon’.
We feel that something is amiss….
APPENDIX: Individual trial information:
- CABP TRIAL 3101 LEAP-1 Lefamulin vs Moxifloxacin
- enrolled 551 patients at 66 centers across 18 countries
(99 centers, 7 in the USA according to clinicaltrials.gov) - stratification planned by geographic region (U.S. versus non-US) but not implemented as only 3 subjects were from the United States
- TRIAL 3102 – LEAP-2 Lefamulin vs Moxifloxacin
- 738 subjects with CABP in 99 centers
(155 centers, 25 in the USA according to clinicaltrials.gov)
- Study CABP1200 – Omadacycline vs Moxifloxacin
- Globally 86 sites enrolled/randomized at least 1 patient.
- Most sites were in EE which accounted for 82.4% of enrollment.
- There was only 1 site in the US which enrolled 3 patients
(140 centers, 12 activated in the US according to clinicaltrials.gov)
ABBREVIATIONS
CABP community-acquired bacterial pneumonia
CAP community-acquired pneumonia
CDCP Centers of Disease Control and Prevention
CMS Centers for Medicare & Medicaid Services
ECR Early Clinical Response
EE Eastern European
TOC Test-of-Cure
REFERENCES
[1] Bart S. Concordance of Early and Late End Points for Community-acquired Bacterial Pneumonia Trials. Clin Infect Dis 2021; 73: e2607–12
[2] DRAFT FDA Guidance Document Community-Acquired Bacterial Pneumonia: Developing Drugs for Treatment. January 2014
[3] FDA Center for Drug Evaluation and Research (CDER) June 2020. Community-Acquired Bacterial Pneumonia: Developing Drugs for Treatment. Guidance for Industry
[4] Clinicaltrials.gov Lefamulin LEAP studies (accessed 7/17/25)
[5] This time window was later changed to 6 hours
[6] CDCP. Annual number and percent distribution of ambulatory care visits by setting type according to diagnosis group: United States, 2009–2010. Available at: https://www.cdc.gov/nchs/data/ahcd/combined_tables/2009-2010_combined_web_table01.pdf. Accessed 3 July 2020.
