The Biggest Change in Clinical Trials Starts with Sponsors

But Without Better Support, Sites Risk Falling Behind 

Clinical research is sprinting toward ICH E6(R3). Principles and Annex 1 are now final, with Annex 2 still in draft. The message is clear, with real accountability for how work gets done on the ground.  

But if sponsors expect the biggest transformation, why do many investigator sites feel the heaviest lift? 

What R3 Really Changes and Why Sites Feel It First 

E6(R3) reframes GCP around fit‑for‑purpose quality, “critical‑to‑quality (CtQ) factors,” and risk‑proportionate oversight. It expands guidance on data governance and clarifies responsibilities across IRB/IEC, investigators, and sponsors (Annex 1). In practice, that means fewer routine box‑checks and more targeted controls, if your people, processes, and tech can support them. 

Proportionate, Not One‑Size‑Fits‑All 

E6(R3) builds directly on ICH E8(R1): design quality in, focus on what truly matters, and manage risk to CtQ factors. That shift should reduce site busywork, but only when sponsors co‑design CtQ with sites and adjust monitoring to real risk.  

Where the Rubber Meets the Road 

The draft Annex 2 pushes practical considerations for decentralized or pragmatic elements and real‑world data. Those choices often move tasks from monitors to coordinators, or from clinics to homes, impacting site staffing, training, and technology readiness.  

Sponsors Are Re‑Tooling, Are Sites Resourced? 

Evidence says site burden is rising. A Tufts CSDD study found half of sites view DCT solutions as more burdensome than traditional approaches; many had little hands‑on DCT experience.  

It isn’t just tech. WCG’s 2024 site survey shows complexity is the number 1 pain point (ahead of staffing and start‑up). Their synthesis highlights a Tufts finding: 70% of global site staff say clinical trials are much harder to manage than five years ago. 

And protocol complexity isn’t abstract: Tufts reports surges in endpoints and procedures, longer cycle times, and soaring amendments, each one ripples into site workflows. 

Bottom line: E6(R3) asks for smarter, not heavier, oversight. But without site‑first support, smarter on paper can become heavier in practice. 

What E6(R3) Actually Expects Sponsors To Do For Sites 

E6(R3) expects risk based quality management (RBQM). Sponsors must identify CtQ factors, perform risk assessment and management, set Quality Tolerance Limits (QTLs), and implement proportionate monitoring (including centralized techniques), with clear data governance and vendor oversight. Execution lives where investigators and coordinators work.  

Regulators reinforce this across regions: 

• FDA: implement risk‑based monitoring with dynamic reassessment, leverage centralized monitoring to reduce missing data and protocol deviations.  

• EMA/EU CTR: adopt risk‑proportionate approaches to monitoring and trial management; tailor oversight to trial risk.  

• MHRA: inspections emphasize proportionate quality management and computerised systems readiness aligned to E6(R3). [gov.uk], [icr-global.org] 

If sites are underpowered, sponsors can’t meet these expectations, no matter how good the SOPs look. 

Five Site‑First Moves To Close the Gap 

1) Co‑design CtQ factors, with the people who run the visits 

Workshop CtQ with site PIs and coordinators before protocol lock. Map procedures to staff time and patient flow; drop non‑CtQ data. That’s E8(R1) in action and enables proportionate controls in E6(R3).  

2) Publish a shared risk register and make it visible to sites 

Maintain a living, study‑level risk log with identified risks, KRIs and QTLs and give sites access. This supports centralized monitoring and faster, transparent escalations. 

3) Centralized monitoring that gives back time 

Use centralized analytics to detect trends and reduce low‑value SDV/SDR.  

4) Rationalize the tech stack around the site 

Audit sponsor‑provided tools for login sprawl, duplicate data entry, and training load. Regulatory guidance allows proportionate oversight, don’t create burdens that CtQ doesn’t justify. 

5) Resource what you require 

If your design adds home health, tele‑visits, or complex labs, budget and train accordingly. This is how you turn “fit‑for‑purpose” from a slogan into fewer deviations and better data.

OPRA RBQM Technology 

You don’t fix the readiness gap with dashboards alone. But RBQM technology like OPRA can remove friction that E6(R3) exposes: 

• Design & Planning: Capture CtQ decisions during protocol development; link each CtQ to KRIs/QTLs so monitoring aligns with purpose from day one. 

• Centralized Monitoring Hub: Ingest EDC, ePRO, lab, and operational signals; surface site‑level heatmaps so CRAs can intervene early and proportionately, based on potential risk indicators. 

• Site‑Facing Views: Give coordinators concise, actionable signal summaries, not just sponsor analytics. This supports the fitness‑for‑purpose principle and reduces back‑and‑forth. 

• QTL Governance: Track thresholds and deviations, with an audit trail mapped to Annex 1 responsibilities. 

 What “Good” Looks Like 

A KRI spikes for missed windows at a high‑enrolling site. OPRA flags at‑risk participants and the upstream driver. The CRA swaps an on‑site visit for a brief process check, ships backup kits, and adds a short staff huddle. The KRI normalizes without blanket SDV or extra visits, quality, proportionately delivered.  

Actions You Can Take 

• Quality by Design & CtQ: Co‑design CtQ with sites; remove non‑CtQ endpoints. 

• Data Governance: Define data lineage and access; minimize duplicate entry for sites. 

• Transparency & Documentation: Maintain a shared risk/QTL log and inspection‑ready audit trails. 

• Risk-Based Approach: Combine centralized monitoring with targeted on‑site checks. 

The Takeaway 

Sponsors own the mandate. Sites carry the workload. E6(R3) gives us permission, and pressure, to focus on what matters. The fastest way to comply and perform is to invest in site‑focused resources and RBQM tooling that reduces burden.