How do pharma, biotech and MedTech companies ensure compliance in clinical trials?
We secure the regulatory quality of clinical trials in line with ICH E6 (GCP), EU 536/2014 (CTR) and EU 2017/745 (MDR): from GCP gap analysis through clinical audits at investigator sites and CROs to TMF review and inspection readiness. Inspections rarely fail because of a single protocol deviation, but because of the Trial Master File: through timestamps and audit trail, inspectors reconstruct whether the TMF was maintained throughout the trial or only backfilled shortly before the inspection.
- Pharma
- Biotech
- MedTech
Overview
What compliance risks arise in clinical trials?
Compliance across drug and medical device trials · ICH E6 (GCP), EU 536/2014 (CTR), EU 2017/745 (MDR), ISO 14155:2020
Last updated: 2026-06-12
Clinical compliance connects three layers that tend to drift apart in day-to-day trial conduct: what the protocol promises, what happens at the investigator sites and what the Trial Master File documents. The points at which trials are most often regulatorily vulnerable:
- GCP requirements under ICH E6 are not fully implemented in daily operations: risk-based quality management (ICH E6(R2) Section 5.0, further sharpened in ICH E6(R3)) exists on paper but governs neither monitoring nor escalation of deviations.
- The Trial Master File is incomplete or not structured to be inspection-ready: essential documents under ICH E6 must be filed throughout the trial, and a structure based on the DIA TMF Reference Model is what makes completeness verifiable in the first place.
- Safety reporting misses deadlines: SUSAR reports and the annual safety report under EU 536/2014 Art. 41–43 for drug trials, the event reporting system under MDR Art. 80 for clinical investigations of medical devices.
- Multiregional trials (EU, US, additional markets) follow different rulebooks: CTR and CTIS in the EU, 21 CFR Part 312 (IND) and Part 812 (IDE) in the US, plus national requirements that must be coordinated centrally.
- Sponsor oversight of CROs is missing or undocumented: under ICH E6, responsibility for the trial remains with the sponsor, even when tasks are fully delegated.
Services
How we support you
GCP Gap Analysis & Compliance Program
Assessment of the GCP compliance level of a trial or of the entire clinical program against ICH E6, EU 536/2014 and national requirements. Deliverable: gap analysis report with a prioritized action plan.
Clinical Audits at Investigator Sites, CROs and Laboratories
Sponsor audits of protocol adherence, data quality and TMF completeness. Deliverable: audit plan, audit report with findings and CAPA recommendations, plus follow-up tracking through to closure of the actions.
Trial Master File: Build-Up, Review & Remediation
Build-up of an inspection-ready TMF based on the DIA TMF Reference Model, documented completeness review and remediation before trial closure or inspection, support for eTMF implementation.
Inspection Readiness Clinical
Preparation of the sponsor site and investigator sites for GCP inspections by the FDA, EMA and national authorities. Deliverable: mock inspection with report, trained study personnel, inspection playbook.
Learn more →Safety Reporting & Pharmacovigilance in Trials
Build-up and review of the processes for SAE capture, SUSAR reporting and annual safety reports under EU 536/2014 Art. 41–43, as well as for the reporting system under MDR Art. 80. Deliverable: reviewed reporting SOPs.
Learn more →Clinical Investigations under the MDR
Compliance support for clinical investigations under MDR Art. 62 ff., Annex XV and ISO 14155:2020, including PMCF studies under Annex XIV Part B. Deliverable: conformity check of the investigation documentation.
Learn more →How we work together
What it comes down to
Clinical compliance is difficult because three threads have to stay in sync over the years: the protocol as the promise, trial conduct at the investigator sites as the reality and the Trial Master File as the proof. Any gap between these threads becomes visible during the inspection, and does so retrospectively: a TMF cannot be turned into one maintained throughout the trial after the fact, because timestamps and audit trail document the sequence in which documents were filed. The limiting factor is therefore almost never the knowledge of ICH E6, EU 536/2014 or the MDR (EU) 2017/745, but the point in time at which compliance structures are in place: before the first patient, not before the first inspection.
That is exactly how we sequence the work. The GCP gap analysis at trial start shows which thread is critical before the monitoring concept and TMF structure are locked in. Audits at investigator sites and CROs run during the trial, while CAPAs can still take effect, not only after database lock. And the mock inspection comes before the real one, so that the team experiences findings in a dry run rather than in the real event. This shifts the effort forward, to where corrections are inexpensive and put no trial data at risk.
Our approach
Our approach
Step
Result
Compliance Assessment
Gap analysis report: where the trial stands against ICH E6, CTR or MDR, and which gaps are inspection-critical.
Remediation Plan
Prioritized action plan with responsibilities, deadlines and CAPA logic, aligned with the study team and QA.
TMF Review & Remediation
Documented completeness review based on the DIA TMF Reference Model, closed gaps, inspection-ready TMF.
Audits
Conducted audits at investigator sites, CROs and laboratories with audit reports, CAPA recommendations and follow-up tracking.
Inspection Readiness
Mock inspection with report, trained investigators and study teams, defined roles and procedures for inspection day.
Ongoing Compliance Support
Periodic reviews of deviations, safety reporting deadlines and TMF status over the course of the trial.
Common pitfalls
Where projects commonly fail
The Trial Master File is maintained retrospectively.
If documents are only collected shortly before the inspection, the audit trail of the eTMF shows exactly that. A TMF must be maintained throughout the trial, otherwise the inspector asks how the sponsor claims to have overseen the trial without up-to-date documentation.
Sponsor oversight of the CRO exists only in the contract.
Under ICH E6, the sponsor remains responsible for the trial, even under full delegation. If the oversight plan, documented reviews of monitoring reports and escalation paths are missing, this is a standard finding in GCP inspections.
Protocol deviations are collected but not assessed.
Recurring deviations of the same kind without root cause analysis and CAPA demonstrate to the inspector a systemic problem in the quality management under ICH E6, not just isolated errors at a single site.
Risk-based monitoring is introduced without documenting the risk assessment.
Reduced source data verification is permissible under ICH E6(R2) Section 5.0, but only on the basis of a traceable, documented risk analysis. Without it, the reduced monitoring looks like a failure to oversee the trial.
In multiregional trials, safety reporting deadlines are managed centrally but not checked per jurisdiction.
EU 536/2014 Art. 41–43, 21 CFR Part 312 and national requirements set different deadlines and recipients. A central SOP without country-level reconciliation produces systematic late submissions.
FAQ
Frequently asked questions
Sources
- ICH E6(R2) and ICH E6(R3) Good Clinical Practice: primary text
- Regulation (EU) 536/2014 (Clinical Trials Regulation): primary text, Art. 41–43, 58
- Regulation (EU) 2017/745 (MDR): primary text, Art. 10, 62 ff., 80, Annex XIV, XV
- ISO 14155:2020: Clinical investigation of medical devices for human subjects, Good Clinical Practice
- 21 CFR Part 312 / Part 812 (FDA)
- DIA TMF Reference Model
- /Users/MWeber/Documents/entourage-website-writer/output/expertise-pages/regulatory-compliance/clinical-compliance/clinical-compliance.md (source material)
- https://theentourage.de/expertise/clinical-compliance/ (existing page content, revised)
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Case Studies
What this looks like in practice
Regulations & standards considered
- ICH E6(R2) (Good Clinical Practice)
- ICH E6(R3) (Good Clinical Practice)
- EU 536/2014 (Clinical Trials Regulation) Art. 41–43, Art. 58
- EU 2017/745 (MDR) Art. 62 ff. (clinical investigations)
- MDR Art. 80 (recording and reporting of events in clinical investigations)
- MDR Annex XIV Part B (PMCF)
- MDR Annex XV (clinical investigations)
- ISO 14155:2020 (clinical investigation of medical devices for human subjects)
- 21 CFR Part 312 (FDA, Investigational New Drug)
- 21 CFR Part 812 (FDA, Investigational Device Exemption)
Related topics
Pharmacovigilance →
Safety reporting in trials and after marketing authorization
MDR Consulting →
Clinical evaluation and clinical investigations under EU 2017/745
Health Authority Interaction →
Preparation and support for regulatory inspections
Post-Market Surveillance →
PMCF and continuous market surveillance after marketing authorization
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