EU Clinical Trials Regulation (CTR 536/2014)

Article 25 sets the application dossier contents (Annex I). Article 26 sets language requirements (the Reporting Member State accepts English for Part I; Part II language is determined by each Member State concerned, with Member States permitted to accept English). Article 27 empowers the Commission to adopt delegated acts updating Annex I.

• Complete Annex I dossier submission
• Language compliance per Member State (national-language portions of Part II)

• Submission with missing Annex I sections
• Use of unaccepted language for Part II sections

Article 10 requires specific consideration for vulnerable populations during assessment: women of childbearing potential / pregnant or breastfeeding women, persons unable to give informed consent, minors, and persons in emergency situations. The protocol must justify their inclusion, the risk-benefit balance and the safeguards employed.

• Vulnerable-population justification in the protocol with risk-benefit analysis and tailored safeguards
• Specific informed-consent documentation appropriate to the population

• Inclusion of vulnerable populations without an Article 10 justification or appropriate safeguards

Article 15 establishes that substantial modifications require prior authorisation. Article 16 sets the application requirements (submission via CTIS). Article 17 sets the 6-day validation period for substantial-modification applications. Articles 18-24 cover the Part I / Part II / combined assessment, decision, and persons-assessing-the-application provisions for substantial modifications.

• Internal procedure to classify modifications as substantial vs non-substantial
• CTIS substantial-modification application records
• Tracking of substantial-modification authorisation status before implementation

• Implementation of a substantial modification before authorisation
• Misclassification of substantial modifications as non-substantial

Article 4 establishes the prior-authorisation requirement: every clinical trial must be subject to scientific and ethical review and authorised in accordance with the Regulation. Article 5 governs application submission via the EU portal (CTIS): the sponsor proposes a Reporting Member State and submits a single application dossier (Part I + Part II). The proposed Member State has 6 days to (a) accept itself as Reporting Member State or (b) inform the sponsor that another Member State has agreed to act as Reporting Member State; the validation phase runs for 10 days.

• CTIS sponsor registration and access
• Application dossier submitted via CTIS
• Validation-phase response handling procedure

• Initiation of a clinical trial without an Article 4 authorisation
• Submission through any channel other than CTIS

Article 6 governs the Part I scientific assessment (jointly assessed by the Member States concerned and led by the Reporting Member State): therapeutic and public-health relevance, design quality, risk-benefit balance, compliance with manufacturing/import provisions, compliance with labelling, completeness and adequacy of the investigator's brochure. Article 7 governs the Part II assessment (each Member State concerned individually): informed consent, recruitment arrangements, compensation, suitability of investigators/sites, damage compensation, data-protection rules, biological samples management, financial-flow disclosure.

• Sponsor responses to Part I and Part II requests for information
• Internal tracking of Reporting Member State communications and decisions

• Delays in responding to RfI / RFM communications that risk implicit refusal

Article 8 sets the decision regime. Each Member State concerned notifies the sponsor through CTIS whether the trial is (a) authorised, (b) authorised subject to conditions, or (c) refused. Refusal is possible only on the specified grounds (Part I disagreement with Reporting Member State conclusions; Part II grounds incl. national-law incompatibility, subject-safety risks, etc.). The decision is final at Member State level, subject to national appeal procedures.

• Conditions-of-authorisation tracking (where applicable to the protocol)
• Records of national appeal procedures where a refusal is challenged

• Implementation of conditions not formally documented and signed off

Article 80 establishes the EU portal as the single entry point for the submission of data and information relating to clinical trials in the Union (the public-facing layer of CTIS). Article 81 establishes the EU database for clinical trials (the regulatory-facing layer of CTIS). Article 82 governs the functionality of the EU portal and the EU database: data quality, public access to the public layer, confidentiality of commercially confidential information (CCI), personal data protection, and data redaction rules. The Agency operates the EU portal and EU database in collaboration with the Member States and the Commission.

• CTIS sponsor user-management procedure
• CCI / personal data redaction procedure for documents submitted to CTIS
• Transparency-monitoring program tracking what is in the public CTIS view

• Documents submitted to CTIS without applying redactions
• No internal tracking of what becomes public in CTIS and when

Article 83 requires each Member State to designate a national contact point. Article 84 sets the Agency and Commission roles in supporting the cooperation between Member States. Article 85 establishes the Clinical Trials Coordination and Advisory Group (CTAG), composed of representatives of the national contact points, advising the Commission and the Member States on the application of the Regulation.

• Identification of the national contact point for each Member State where the sponsor operates

Article 93(1) provides that the Regulation applies without prejudice to GDPR for the processing of personal data carried out in the Union for the purposes of the Regulation. Article 93(2) requires Member States to apply the GDPR national-derogation rules to the processing of personal data in clinical trials. Article 93(3) governs the processing of personal data within the EU portal and the EU database. The sponsor and the investigator process subject personal data (including special-category health data) under Article 6 + Article 9(2)(i) (public health) or Article 9(2)(j) (scientific research) GDPR.

• GDPR legal-basis analysis for the trial (Article 6 + Article 9 GDPR)
• Article 14/13 information notices to subjects
• Records of any GDPR derogations under Article 89 GDPR for scientific research

• Reliance on consent under GDPR Article 6(1)(a) alone for clinical-trial data processing (consent under the GDPR is distinct from informed consent for trial participation)
• No GDPR DPIA for high-risk processing (e.g. genetic data, large multi-country trials)

Article 94 requires Member States to lay down penalties applicable to infringements of the Regulation, including (a) compliance with the conditions on subject protection and informed consent; (b) compliance with the conditions on safety reporting; (c) compliance with the conditions on the conduct of the trial; (d) other relevant provisions. The penalties must be effective, proportionate and dissuasive.

• Awareness of the applicable national-law penalty regime in each Member State where the sponsor operates
• Compliance program demonstrating proactive risk management against the penalty regime

Article 47 requires the sponsor and the investigator to ensure that the clinical trial is conducted in accordance with the protocol and the principles of good clinical practice (GCP). The reference document for GCP in the EU is the ICH GCP guideline (currently E6(R3)) as adopted by the Commission. Sponsors and investigators must comply with the protocol, GCP and the applicable scientific guidelines.

• Sponsor and investigator GCP-training records
• Protocol-compliance monitoring records
• ICH E6(R3) alignment evidence in the quality management system

• Sponsor with no documented GCP quality management system
• Site activations without GCP-training records for the investigator team

Article 48 requires the sponsor to monitor the conduct of the trial in order to verify that the rights, safety and well-being of subjects are protected, that reported data are reliable and robust, and that the trial is conducted in accordance with the protocol, GCP and applicable Union law. The extent and nature of monitoring is determined by the sponsor based on a risk-based approach taking into account the characteristics of the trial (the risk-based monitoring principle, aligned with ICH E6(R3) A1.7).

• Risk-based monitoring plan for each trial
• Monitoring visit reports and resolution of findings
• Risk-assessment documentation supporting the chosen monitoring strategy

• 100% source-data verification without a risk-based justification
• No monitoring visits for the duration of a multi-year trial

Article 52 requires the sponsor to notify the Member States concerned within 7 days of a serious breach of the Regulation or the version of the protocol applicable at the time of the breach. A 'serious breach' is one likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated by the trial.

• Internal escalation procedure to classify and report serious breaches within 7 days
• Serious-breach log and CTIS notification records
• Root-cause analysis and CAPA records

• Late or omitted serious-breach notifications
• No internal definition aligned to Article 2 'serious breach'

Article 57 requires the sponsor and the investigator to keep a clinical trial master file (TMF) containing the essential documents that demonstrate compliance with the Regulation and the principles of GCP. Article 58 requires the TMF to be archived for at least 25 years after the end of the trial, unless other Union law requires a longer archiving period. The personal data of subjects in the TMF is deleted at the end of the archiving period.

• TMF inventory and indexing demonstrating completeness
• Archiving plan covering the 25-year retention period
• Personal-data deletion procedure at the end of archiving

• TMF with gaps in essential documents
• No 25-year archiving plan or no deletion plan for subject personal data

Article 61 requires manufacturing and import of investigational medicinal products to be subject to authorisation by the Member State of manufacture/import. Article 62 sets the responsibilities of the qualified person (QP) for IMP release. Article 63 sets the GMP requirements for the manufacture and import of IMPs (the Commission has adopted the IMP-specific GMP via Commission Delegated Regulation (EU) 2017/1569 + the EU GMP Guide Annex 13).

• IMP manufacturing/import authorisation per Article 61
• QP-release records per Article 62 and Article 63
• GMP compliance evidence per the IMP-specific GMP (Reg 2017/1569 + Annex 13)

• Distribution of IMP to sites without QP release records
• IMP manufacturing site not authorised under Article 61

Articles 66-69 set the labelling requirements for IMPs (Annex VI to the Regulation): unauthorised IMPs, authorised IMPs used as IMPs, and radiopharmaceuticals. Article 69 governs the language of labelling (determined by the Member State concerned, with English permitted where the Member State so allows).

• IMP label artwork demonstrating Annex VI compliance
• Member-State-specific language label sets
• Records of any Article 67(2) simplification permitted for authorised IMPs used as IMPs

• IMP labels missing required Annex VI elements
• Label language not aligned with the Member State of conduct

Article 1 establishes the scope: the Regulation applies to all clinical trials conducted in the Union. It does not apply to non-interventional studies. Clinical trials defined in Article 2 are within scope; the boundary with low-intervention clinical trials is a key application question.

• Documented scope determination for the entity's research (interventional clinical trial vs low-intervention vs non-interventional study)

• Treating an interventional clinical trial as a non-interventional study to avoid CTR scope

Article 2 supplies definitions, including 'clinical study', 'clinical trial', 'low-intervention clinical trial', 'non-interventional study', 'investigational medicinal product (IMP)', 'auxiliary medicinal product', 'sponsor', 'investigator', 'subject', 'informed consent', 'protocol', 'serious adverse event', 'serious adverse reaction', 'suspected unexpected serious adverse reaction (SUSAR)', and 'serious breach'.

• Definitions glossary aligning the entity's internal terminology to Article 2 (in particular 'low-intervention clinical trial', 'SUSAR', 'serious breach')

• Inconsistent SUSAR/SAE definitions across protocols

Article 3 sets the overarching ethical and scientific principle: a clinical trial may be conducted only if the rights, safety, dignity and well-being of subjects are protected and prevail over all other interests, AND the trial is designed to generate reliable and robust data. This principle underpins every operational article of the CTR.

• Protocol-level statement of the Article 3 principle and how it is operationalised
• Independent ethics review evidence confirming Article 3 compliance

• Protocols that do not articulate the Article 3 subject-rights-prevail principle

Article 71 establishes that a clinical trial may have one or several sponsors, and that the sponsor may delegate any or all of its tasks (but remains responsible). Article 72 governs co-sponsorship (joint and several liability for compliance unless a written contract allocates obligations and the trial subjects are informed). Article 73 establishes the principal investigator role. Article 74 requires the sponsor (where established outside the Union) to be represented by a legal representative established in the Union.

• Sponsor declaration in CTIS
• Co-sponsor agreement (where co-sponsorship is declared)
• Legal-representative appointment evidence where the sponsor is non-EU

• Delegation of sponsor obligations without a written agreement
• Non-EU sponsor operating without an Article 74 legal representative

Article 76 requires Member States to ensure that systems for compensation for any damage suffered by a subject resulting from participation in a clinical trial are in place in the form of insurance, guarantee or similar arrangement. Member States are entitled to operate a national indemnification mechanism for low-intervention clinical trials (or other-than-low-intervention trials where Member State law so provides).

• Subject-damage compensation arrangement (insurance certificate or national-mechanism participation) for each Member State concerned
• Compensation arrangements communicated to subjects (Article 29(2)(j) information)

• No compensation arrangement in place at the time the first subject is included
• Compensation arrangement that does not extend to all Member States concerned

Article 77 empowers Member States to take corrective measures: revoke the authorisation, suspend the trial, require the sponsor to modify any aspect of the trial. Article 78 requires Member States to perform inspections to monitor compliance with the Regulation. Article 79 enables Union-level controls by the Agency and the Commission in third countries and within the Union.

• Inspection-readiness records (TMF inventory, audit trails, training records, monitoring plan execution)
• Corrective-action records following any Member State inspection finding

• No inspection-readiness program despite multi-year multi-site trials
• CAPA backlog from prior inspections

Article 36 requires the sponsor to notify, through CTIS, the start of a clinical trial, the start of recruitment of subjects, and the first visit of the first subject. Article 37 requires the sponsor to notify the end of the trial in each Member State concerned (within 15 days) and the end of the trial in all Member States (within 15 days), together with the summary of results within 1 year (or 6 months for paediatric trials, plus a lay summary). Article 37(4) requires the summary of results to be submitted within 30 days of trial termination/halt.

• CTIS notifications calendar for the start/recruitment-start/first-visit/end-of-trial events
• Summary of results submitted within Article 37 timeframes
• Lay summary in CTIS

• Missed CTIS notification deadlines
• Summary of results submitted late or omitted (the CTIS-public-portal transparency obligation)

Article 38 requires the sponsor to notify the Member States concerned within 15 days of a temporary halt or early termination of the clinical trial for reasons of subject safety. The notification must include the reasons, follow-up measures for enrolled subjects, and the safety-information dissemination plan.

• Internal safety-board procedure that can trigger an Article 38 halt
• Records of any Article 38 notifications with corrective measures

• Safety halt decisions not promptly notified via CTIS

Article 41 requires investigators to record and report adverse events and serious adverse events specified in the protocol to the sponsor within specified timeframes. Article 42 requires the sponsor to report SUSARs to the Agency (EMA, via EudraVigilance) without undue delay: fatal/life-threatening SUSARs within 7 days, other SUSARs within 15 days, including follow-up reports within 8 days from the initial report.

• Investigator AE/SAE reporting records aligned to the protocol
• SUSAR submissions to EudraVigilance within Article 42 timelines (7/15 days)
• Follow-up SUSAR submissions and reconciliation

• Late SUSAR reports
• SUSARs not classified or escalated correctly

Article 43 requires the sponsor to submit annually to the Agency, for each IMP, an annual safety report (development safety update report, DSUR) for the duration of the clinical trial. The report is submitted via EudraVigilance and contains a summary and critical assessment of all relevant new safety information.

• Annual DSUR submission for each IMP for each year of the trial
• DSUR critical-assessment narrative

• Missed DSUR submission anniversary
• DSUR without critical assessment

Article 28(1) sets the cumulative conditions for any clinical trial: (a) the anticipated benefits to subjects or public health justify the foreseeable risks and inconveniences; (b) subjects are protected through the procedures in this Chapter; (c) the rights, safety, dignity and well-being of subjects prevail over all other interests; (d) the trial is designed to generate reliable and robust data; (e) any risk to subjects is mitigated to the maximum extent; (f) the protocol is approved; (g) subjects benefit from medical care without charge for direct trial-related procedures.

• Risk-benefit assessment in the protocol
• Subject-rights statement and medical-care coverage records
• Risk-mitigation plan with specific measures

• Risk-benefit assessment that does not address each Article 28(1) cumulative condition

Article 29 sets the informed-consent rules. Consent must be: in writing, dated, signed; freely given after the subject has been informed of the nature, objectives, benefits, implications, risks and inconveniences of the trial; given without compulsion; revocable at any time without detriment. Article 29(2) requires that the information is comprehensive, concise, clear, relevant and understandable to a layperson and includes specific items listed in Article 29(2)(a)-(k). Subjects may request a copy. Article 29(5) governs the case where the subject is unable to read.

• Subject-information sheet and informed-consent form aligned to Article 29(2)(a)-(k)
• Investigator-signed records of the informed-consent discussion
• Consent-withdrawal procedure

• Information sheet missing items required by Article 29(2)
• Coerced consent (financial incentive disproportionate to inconvenience)
• No mechanism to handle consent withdrawal mid-trial

Article 31 governs clinical trials on incapacitated subjects: trial must be essential with respect to the incapacitated population, expected benefits to the population must outweigh the risks, and consent is given by the legally designated representative with the subject's assent where possible. Article 32 governs clinical trials on minors: similar safeguards with assent of the minor where age-appropriate, and the protocol must contain specific provisions for the minor's age and maturity.

• Capacity-assessment records and legal-representative consent documentation
• Age-appropriate assent procedures for minors
• Population-specific protocol provisions

• Inclusion of incapacitated subjects without legally designated representative consent
• No assent procedure for minors where assent is feasible

Article 33 governs clinical trials on pregnant or breastfeeding women. Article 34 permits Member States to maintain additional measures on persons performing military service / persons deprived of liberty / persons residing in institutions / pregnant women / breastfeeding women. Article 35 governs clinical trials in emergency situations (deferred consent procedure where the subject's clinical condition does not allow prior consent, subject to strict safeguards including subsequent confirmation by the subject or the legal representative).

• Pregnancy/breastfeeding-specific risk-benefit assessment where included
• Article 35 emergency-trial procedure with deferred-consent safeguards and subsequent confirmation

• Emergency-trial enrolment without the Article 35(1)(a)-(g) cumulative safeguards
• Inclusion of pregnant women without specific protocol justification