One sepsis assay, seven separate enrollment problems

1. Background

the sponsor is a [location redacted]-based molecular diagnostics company developing a host-response classifier for acute infection across anatomical sites. The classifier requires prospective specimens from symptomatic patients with confirmed or suspected acute infection, paired with adjudicated etiology labels (bacterial, viral, mixed, or non-infectious). Specimen collection includes capillary blood (deposited directly into the sponsor’s proprietary DTECT lysis buffer for downstream RNA preservation), venous EDTA-stabilised blood, and venous PAXgene RNA-stabilised blood — up to 50 mL total venous draw at the enrollment visit, with pediatric volume rules from age 12 / 17 kg.

Unlike single-syndrome respiratory IVD studies, study enrolls across seven anatomical infection strata: acute respiratory, intra-abdominal, skin and soft tissue, bone and joint, urinary tract, central nervous system, and febrile illness without clear source. Each stratum has its own clinical signature, screening pattern, and adjudication algorithm. Adjudication operates weekly against the sponsor’s FDA-approved Clinical Adjudication Charter — the protocol’s gold standard for etiology assignment — rather than against an ad-hoc clinical reference algorithm constructed for the study.

2. Constraints encountered

Five constraints shaped the execution plan:

1. Multi-syndromic eligibility envelope

   Enrollment ran in parallel across seven anatomical strata. Acute respiratory and febrile-unclear-source pulled patients from a shared clinical front door (ED, urgent care). Skin and soft tissue, urinary tract, and intra-abdominal pulled from distinct sub-populations; bone, joint, and CNS infections were rare-event strata where individual case identification mattered more than channel volume.

2. Adjudication latency on the critical path

   The dataset is etiology-labelled by the adjudication committee, not by the EDC. Adjudication latency — the time from enrollment to a final adjudicated label — is the critical-path metric, not enrollment count. Out-of-window SOFA scores and incomplete source documents were the principal sources of delay early in the program.

3. Sponsor-supplied collection buffer with finite stability

   Capillary samples were collected directly into the sponsor’s proprietary DTECT lysis buffer; estimated stability of approximately three months from manufacture. Buffer inventory at the site had to be replenished on a one-week notice cadence; expired buffer would have failed the sample.

4. RNA-grade specimen processing in the field

   PAXgene Blood RNA tubes preserve transcriptomic signal but require centrifuge processing within 15 minutes of draw. Both sites required calibrated refrigerated centrifuges, plasma isolation SOPs, and RDI day-of-collection notification before draws to coordinate cold-chain and shipping windows.

5. Sequential site activation

   Site A activated first as the lead site; Site B required Advarra IRB reliance from its local IRB before it could be added to the study. The reliance window pushed Site B’s first enrollments to late April 2026, three months after Site A was producing steady weekly volume.

3. Methods

RDI executed the program as full-service CRO from the Van Nuys spine: site identification, IRB submission and ongoing maintenance, kit production with sponsor-supplied buffer, central monitoring, and weekly case packaging for the sponsor adjudication committee. Five operational moves are reported here in order of implementation.

3.1. Compressed IRB pursuit

The Advarra IRB application ([Pro number]) was filed 12 September 2025. IRB review cleared 19 September 2025 — 7 days end-to-end. Approval documents were posted 30 September 2025; site startup at Site A began immediately. Holiday-window IRB pursuit was not a constraint here, but the same cadence was maintained against post-IRB amendments and Site B onboarding.

3.2. Lead site activation at Site A

Site A was activated as the lead site in late October 2025. Site initiation included sponsor adjudication training (12 January 2026 with sponsor and RDI co-facilitating), kit design verification, EDC training, and deployment of the study kit-making and shipment workflow that ultimately produced 134 subjects through the end of April 2026.

3.3. Adjudication committee operating under FDA-approved Charter

Adjudication was performed weekly by the sponsor’s independent adjudication committee under the sponsor’s FDA-approved Clinical Adjudication Charter. RDI’s role was source-document collection, data abstraction into the EDC, and weekly case packaging for the committee. Operating against a pre-existing, FDA-aligned charter rather than constructing one mid-study removed an entire class of methodological rework that this kind of multi-syndromic study commonly requires.

3.4. Out-of-window SOFA reconciliation

Early in the program, out-of-window SOFA scores accounted for a meaningful portion of pending-adjudication backlog. RDI worked with sites and sponsor to confirm that out-of-window SOFA scores would not be obtained retroactively and updated open queries accordingly. The change shortened the average time-to-adjudication for subjects enrolled in March 2026 to a 34-day median.

3.5. Site B activation, Q1–Q2 2026

The fully-executed agreement with Site B was put in place in February 2026. The Advarra reliance request from Site B’s local IRB was the principal time-on-the-clock; Site B first enrolled in late April 2026 (3 subjects in week one). At Site A’s sustained ~7 subjects/week and Site B’s ramp, the program forecasts the 250-subject enrollment goal by late July 2026, assuming Site B contributes approximately 40 of the remaining ~118 subjects.

4. Results

Cumulative enrollment crossed 34 by end-January 2026, 66 by end-February, 97 by end-March, and reached 132 at the 30 April 2026 reporting date (Fig. 1). Distribution by syndrome group at the 30 April reporting cut: acute respiratory 43, febrile illness without clear source 45, intra-abdominal 16, skin and soft tissue 17, bone and joint 2, urinary tract 8, and CNS 1 (Table 1; Fig. 2).

Adjudication committee disposition for the 99 cases adjudicated by the same date: 43 bacterial, 33 viral, 5 mixed bacterial/viral, and 15 with no clear infectious etiology. The bacterial-to-viral ratio at the cohort level (43:33) reflects the multi-syndromic enrollment design — intra-abdominal, skin/soft-tissue, and urinary-tract strata produce a higher prevalence of bacterial etiology than the respiratory and febrile-unclear-source strata that dominated the volume.

Time-to-adjudication shortened across the enrollment window. Subjects enrolled in March 2026 averaged 34 days to adjudication, with one of 33 outstanding at the 30 April cut.

5. Discussion

Three observations bear noting. First, multi-syndromic enrollment is operationally distinct from a single-syndrome study and the operational unit of work is not “subject” but “syndrome”. Acute respiratory and febrile-unclear-source share a clinical front door, but intra-abdominal, skin and soft tissue, urinary tract, bone and joint, and CNS each pull from a distinct screening flow within the institution. The bacterial-to-viral ratio at the cohort level (43:33) is a function of the volume mix across these strata, not of a population-level prevalence figure.

Second, adjudication latency is the critical-path metric, not enrollment count. The dataset that the sponsor uses for assay development is the adjudicated dataset, and the adjudicated dataset is gated by source-document completeness, SOFA-window enforcement, and committee throughput — not by collection cadence at the site. Closing the SOFA-window question (out-of-window scores not retroactively obtained) shortened time-to-adjudication for March-2026 enrollments to a 34-day median, with one case outstanding at the 30 April reporting date.

Third, the sponsor’s pre-existing FDA-approved Clinical Adjudication Charter is the principal lever protecting the analytical pipeline. Operating against an FDA-aligned charter from day one — rather than building one mid-study or after sponsor regulatory feedback — removed a class of methodological rework that this kind of multi-syndromic specimen collection commonly requires. The CRO’s job in that frame is execution against the charter, not adjudication design.

6. Conclusion

Multi-syndromic specimen collection for a host-response sepsis assay is operationally distinct from a single-syndrome respiratory or POC method comparison study. Treating each syndrome group as its own enrollment funnel, executing against a sponsor’s pre-existing FDA-approved Adjudication Charter, and treating adjudication latency — not enrollment count — as the critical-path metric protected the analytical pipeline as the program scaled. The program is on track for late-July 2026 target attainment with the Site A + Site B two-site network now operating.