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chapter 01 · the regulatory spine

The eight GCP pillars · seven regulators.

Quick-reference grid of the eight Good-Clinical-Practice pillars · then the cross-regulator comparison drilldown for each. ICH E6(R3) Step 4 (6 January 2025) · FDA · EMA · PMDA · CDSCO · MHRA · Health Canada. The flagship chapter for the clinical-trial spine.

/ 00

The deep reference: ICH E6(R3) Step 4.

Adopted 6 January 2025 · live

The clinical-trial spine pivoted on 6 January 2025, when the ICH Assembly adopted E6(R3) at Step 4. R3 is a structural rewrite of the global Good Clinical Practice standard, not an addendum: twelve overarching principles, Annex 1 (Interventional) at Step 4 alongside the principles, and Annex 2 (Non-traditional designs) still in development. The 2016 R2 addendum stays in force until R3 is regionally implemented — regional implementation should be checked against current FDA, EMA, MHRA, PMDA, CDSCO, Health Canada, and other regulator pages before operational reliance.

This chapter sits each of the eight operational GCP pillars against seven regulators side by side. Pick a pillar. Read the convergence/divergence summary. Compare ICH E6(R3) · FDA 21 CFR 312/50/56 · EMA CTR 536/2014 + CTIS · PMDA J-GCP · CDSCO NDCT 2019 · MHRA UK Clinical Trials Regulations · Health Canada Division 5. The pillars were chosen because they repeatedly drive sponsor, site, audit, and inspection-readiness questions.

/ Foundation document

7 regulators · 8 GCP pillars · one reference.

Designed for the sponsor regulatory lead, the QA auditor, the CRO project manager, the cross-region investigator-site. Where regulators converge, the pillar can be read as broadly harmonised. Where they diverge, the divergence is the practical question to verify.

ICH E6(R3)FDAEMA CTRPMDACDSCOMHRAHealth Canada

/ 00a

The twelve overarching principles of E6(R3).

Adopted 6 January 2025

R3 starts with twelve principles that govern every operational pillar below. They do not replace the pillars — they sit above them. R3 is the first GCP text to make quality-by-design, risk proportionality, and participant-centric language doctrinal rather than aspirational. Where Annex 1 is silent, the principles bind.

Conduct in accordance with ethical principles.

Declaration of Helsinki at the apex. Belmont and CIOMS recognised. Local ethics review independent of sponsor.

Informed consent before any trial-related activity.

Voluntary, current, documented. Re-consent on material amendment. Capacity assessment for vulnerable participants.

iii

Independent ethical review (IRB/IEC).

Composition, scope, working procedures, decision documentation. Approval before any participant enrols.

Scientific soundness; clear, detailed protocol.

Protocol drives every other artefact. Pre-specified endpoints; statistical analysis plan locked before unblinding.

Qualified investigators; medical decisions by qualified physicians.

Investigator CV + delegation log. 21 CFR 312.53 in the US; J-GCP investigator qualification dossier in Japan.

Quality by design; risk proportionate to participant.

R3's signature shift. Critical-to-quality factors identified at protocol design, not retroactively at audit.

vii

Operations proportionate to risk.

Risk-based monitoring (RBM) moves the field away from routine 100% SDV toward documented risk proportionality. ICH E6(R2) §5.0 lineage retained.

viii

Reliable trial results.

ALCOA+ data integrity (Attributable, Legible, Contemporaneous, Original, Accurate, plus Complete, Consistent, Enduring, Available).

Roles and responsibilities clear.

Sponsor, investigator, vendor, IRB. Delegation should be documented at the level of the activity.

Investigational products manufactured under GMP.

Storage, handling, accountability traceable. ICH Q7/Q9/Q10 lineage on the product side.

Systems and processes assure quality.

SOPs, training records, vendor oversight, computerised system validation (21 CFR Part 11 / EU Annex 11).

xii

Trial registration and results disclosure.

ClinicalTrials.gov / EU CTIS / Japan jRCT / India CTRI. Lay-summary timing should be checked against EU CTR requirements and trial context.

/ 01

The eight GCP pillars.

The operational spine

These eight pillars are the working surfaces iFeed uses to read whether a clinical trial is GCP-ready and evidence-ready. Below: a quick-reference grid of all eight · then the cross-regulator drilldown for each. Informed consent and safety reporting are where many programmes face recurring inspection and audit questions; data integrity (★) is where the cross-regulator divergence runs deepest in 2026.

Quick reference · the eight pillars.

/ 1.1

Informed consent.

Voluntary, current, documented. ICH E6(R3) Annex 1 §3.3; 21 CFR 50 Subpart B; EU CTR Article 28-31. Re-consent on material amendment. eConsent recognised by FDA and EMA.

/ 1.2

IRB / IEC oversight.

Independent ethics review before enrolment. 21 CFR 56; EU CTR Part II Member State; J-GCP IRB; CDSCO Form CT-04 ethics approval. Composition, quorum, decision documentation.

/ 1.3

Investigator qualification.

CV, training, GCP, delegation log, 1572 (US). 21 CFR 312.53; ICH E6(R3) Annex 1 §2; PMDA investigator dossier. Qualifications should be documented against the protocol's medical demands.

/ 1.4

Monitoring · RBM.

Risk-based monitoring · centralised + on-site. ICH E6(R3) Annex 1 §3.10; FDA RBM Guidance Aug 2013/2023. Critical-to-quality data drive monitoring intensity, not blanket 100% SDV.

/ 1.5

Data integrity. ★

ALCOA+ across paper and electronic. 21 CFR Part 11 + EU Annex 11; MHRA Data Integrity Guidance Mar 2018; PIC/S PI 041-1. Where the regulator divergence runs deepest.

/ 1.6

Safety reporting.

SAE/SUSAR reporting timelines should be mapped by seriousness, expectedness, causality, and jurisdiction. ICH E2A definitions, E2B(R3) electronic submission, E2D post-marketing. EudraVigilance, FAERS, JADER, VigiBase.

/ 1.7

TMF · Reference Model 3.3.

Trial Master File, paper or electronic. ICH E6(R3) Annex 1 §3.16; DIA TMF Reference Model 3.3 (2022); Inspection-ready throughout, not at lock.

/ 1.8

Source documentation.

Source data → CRF traceability. Certified copies, eSource, EHR-to-EDC. ICH E6(R3) Annex 1 §3.15; FDA eSource Guidance Sep 2013; EMA Reflection Paper EMA/INS/GCP/454280/2010.

Cross-regulator comparison · ICH · FDA · EMA · PMDA · CDSCO · MHRA · Health Canada.

ICH E6(R3) FDA 21 CFR EMA CTR 536/2014 PMDA J-GCP CDSCO NDCT 2019 MHRA UK CTR Health Canada Div 5

/ 1.1 Informed consent.Voluntary, current, documented. Re-consent on amendment. eConsent. +

At a glance · convergence vs divergence

CONVERGE

The regulators compared here require documented informed consent before trial-related procedures, with jurisdiction-specific form, witness, electronic-consent, and vulnerable-population rules. Declaration of Helsinki at apex. Re-consent on material amendment.

DIVERGE

EU CTR Article 28-31 mandates a participant-friendly summary plus the full ICF; CDSCO NDCT Schedule III can require audio-video recording for vulnerable populations and trials in illiterate participants; FDA 21 CFR 50.27 permits short-form consent + witness signature; EMA + FDA 2024 Q&A formally recognise eConsent; PMDA J-GCP §50 can require a separate "explanation document" distinct from the consent form.

ICH E6(R3)2025-01-06

Annex 1 §3.3 · principle ii

Voluntary informed consent, current at time of activity. Documented, dated, signed. Capacity-appropriate language. Re-consent on amendment material to participant interest.

Acceptance criteriaPre-trial signature · re-consent on amendment · capacity assessment

FDA21 CFR 50

Subpart B · short-form OK

21 CFR 50.20 · 50.25 elements (8 basic + 6 additional). 50.27 short-form + witness allowed. eConsent per Dec 2016 Q&A; updated 2024.

Acceptance criteria14 elements · witness for short-form · eConsent

EMA CTR536/2014

Article 28-31 · lay summary

CTR Article 28 (general), 29 (informed consent in clinical trials in emergency situations), 30 (incapacitated subjects), 31 (minors). Lay-summary obligations apply under the EU CTR framework.

Acceptance criteriaFull ICF + lay summary · CTIS upload

PMDA J-GCPMHLW 28/1997

§50, 51 · explanation doc

Explanation document distinct from consent form. Reviewed by IRB. Reading-level appropriate. Re-consent triggers explicitly enumerated.

Acceptance criteriaTwo-document model: explanation + consent

CDSCO NDCT2019

Schedule III · audio-video

Rules 16-19 + Schedule III. Audio-video recording requirements can apply for vulnerable populations and illiterate participants under Indian rules; current applicability should be verified before trial start. Form CT-01 acknowledgement.

Acceptance criteriaAV recording for vulnerable groups

MHRA UK CTRSI 2004/1031

Schedule 1 Part 2 · ICH-aligned

UK Clinical Trials Regulations Schedule 1 Part 2. ICH-aligned post-Brexit; HRA/NHS site-level approvals separate from MHRA CTA.

Acceptance criteriaICH-aligned · HRA approval distinct

Health CanadaDivision 5

FDR C.05 · ICH-aligned

Food and Drug Regulations Division 5 (Drugs for Clinical Trials). ICH-aligned consent. REB approval is needed before participant enrolment under the applicable framework under the applicable Canadian framework.

Acceptance criteriaICH-aligned · REB approval

Inspector's eye

For India-bound trials, the AV recording rule under Schedule III can become a significant finding for non-Indian sponsors if not planned correctly. For EU CTIS submissions, the lay-summary upload can become a reason for assessment questions if not planned correctly. Both pre-2019 ICFs and pre-CTIS ICFs often need a refresh.

/ 1.2 IRB / IEC oversight.Independent ethics review · composition · scope · quorum. +

At a glance · convergence vs divergence

CONVERGE

Independent ethics review is a common pre-enrolment requirement across the compared frameworks. Composition: scientific + non-scientific + lay member at minimum. Decisions documented.

DIVERGE

EU CTR moves national ethics into Part II of the CTIS submission — one harmonised dossier, but each Member State runs national ethics in parallel. FDA 21 CFR 56 recognises central IRBs (WCG IRB, Advarra, Salus) for multi-site studies; this is uncommon in EU. Indian Ethics Committee registration and study-specific approval should be checked against current CDSCO and committee requirements.

ICH E6(R3)2025-01-06

Annex 1 §1 · principle iii

Independent ethics review before any trial-related activity. Composition criteria, working procedures, decision documentation, ongoing review at intervals appropriate to risk.

Acceptance criteriaIndependent · documented · ongoing review

FDA21 CFR 56

Central IRB recognised

21 CFR 56 Subparts A-D. Central IRB (WCG, Advarra, Salus) standard for multi-site. Single IRB rule for NIH cooperative research.

Acceptance criteriaCentral IRB OK · FDA 1572 lists IRB

EMA CTR536/2014

CTIS Part II per MS

CTR Article 4-5. Single-portal CTIS submission; Part I scientific assessment (RMS-led); Part II national ethics in each MS. Ireland's NREC, France's CPP, etc.

Acceptance criteriaCTIS Part II · per Member State

PMDA J-GCPMHLW 28/1997

§27-34 · institution IRB

Institution-based IRB the historical norm; central IRB (Joint IRB / shared IRB) recognised since 2017 J-GCP revision. Annual continuation review required.

Acceptance criteriaInstitution IRB · annual continuation

CDSCO NDCT2019

Form CT-04 EC registration

Rules 7-15. Ethics Committee registration on Form CT-04 separate from study approval. Composition: 7-15 members; minimum 1 lay, 1 woman, 1 legal expert.

Acceptance criteriaEC registration distinct from CT approval

MHRA UK CTRSI 2004/1031

REC + HRA

Research Ethics Committee (REC) review via Health Research Authority (HRA). HRA Approval combines REC favourable opinion + NHS R&D capacity confirmation.

Acceptance criteriaREC favourable · HRA Approval

Health CanadaDivision 5

REB approval · TCPS2

FDR C.05.006(1)(c) requires REB approval. TCPS2 (Tri-Council Policy Statement) governs ethics-committee composition and procedures.

Acceptance criteriaREB · TCPS2 compliance

Inspector's eye

For multi-EU-MS trials, the most-flagged Part II finding is misalignment between Member-State ethics opinions on the same protocol; harmonised RMS Part I is no defence. For US-cooperative-group trials, single-IRB rule from NIH cooperative-research policy still surprises non-cooperative-group sponsors.

/ 1.3 Investigator qualification.CV, training, GCP, delegation, 1572 (US) / J-GCP dossier (Japan). +

At a glance · convergence vs divergence

CONVERGE

The compared frameworks require qualified PI by training, education, experience matched to the protocol's medical scope. CV, GCP training, delegation log; medical decisions by a qualified physician.

DIVERGE

FDA Form 1572 Statement of Investigator is the US-specific instrument; PMDA requires institution-level investigator dossier with annual update; Indian investigator and site requirements should be checked against current NDCT/CDSCO provisions; EMA CTR embeds investigator CVs in CTIS Part I but has no equivalent of the 1572.

ICH E6(R3)2025-01-06

Annex 1 §2 · principle v

Investigator qualification: education, training, experience commensurate with protocol's clinical and procedural demands. CV, GCP training, delegation log per activity.

Acceptance criteriaCV · GCP · delegation log per activity

FDA21 CFR 312.53

Form 1572 requirement

312.53(c) Form FDA 1572 Statement of Investigator. Lists IRB, sub-investigators, facilities. False statement = federal felony. Form updated when sub-investigators change.

Acceptance criteria1572 signed · updated on change

EMA CTR536/2014

CTIS Part I CV upload

CTR Article 49(2)(d). Investigator CV in CTIS Part I; no separate signed statement equivalent to 1572. Site-level investigator change reportable as substantial modification.

Acceptance criteriaCV in CTIS · change = substantial modif.

PMDA J-GCPMHLW 28/1997

Institution dossier annual

§42-43. Institution-level investigator qualification dossier; annual update. Sub-investigator delegation documented at institution level.

Acceptance criteriaInstitution dossier · annual update

CDSCO NDCT2019

Rule 17 · pre-registration

Indian investigator, site, CV, and training requirements should be verified against current CDSCO/ICMR expectations before nomination on a CT application.

Acceptance criteriaPre-registration with CDSCO

MHRA UK CTRSI 2004/1031

Schedule 1 Part 4

Investigator brochure + CV in CTA. ICH-aligned. NHS R&D capacity assessment for site-level qualification.

Acceptance criteriaCV + IB · NHS R&D capacity

Health CanadaDivision 5

Canadian Food and Drug Regulations records

Canadian Food and Drug Regulations records of qualifications. ICH-aligned. Qualified Investigator (QI) attestation maintained at site.

Acceptance criteriaQI attestation · ICH-aligned

/ 1.4 Monitoring · risk-based.RBM · centralised + on-site · critical-to-quality data drive intensity. +

At a glance · convergence vs divergence

CONVERGE

Major regulators now support risk-based monitoring principles, moving away from routine 100% Source Data Verification where risk assessment supports a proportionate approach. Critical-to-quality factors define monitoring intensity.

DIVERGE

FDA RBM Guidance (final Aug 2013) + FDA RBM Q&A guidance (final April 2023) formalised RBM ahead of ICH; EU CTR Article 48 (Monitoring; Article 48(2) is the legal basis for risk-based approach to monitoring; RMS assessment governed by Articles 5–8); PMDA historically slower to accept centralised-only monitoring — 2024 J-GCP guidance now aligned; CDSCO expectations for on-site monitoring frequency should be checked against current official and site-risk requirements.

ICH E6(R3)2025-01-06

Annex 1 §3.10 · principle vii

Sponsor monitoring plan based on critical-to-quality factors. Centralised + on-site + remote in any combination justified by risk. Trigger-based escalation.

Acceptance criteriaRisk-based monitoring plan · CtQ factors

FDA2013/2023

RBM Guidance · oversight

A Risk-Based Approach to Monitoring of Clinical Investigations Aug 2013, revised Mar 2023. Monitoring plan part of QMS. 21 CFR 312.50 sponsor general responsibilities.

Acceptance criteriaRBM plan · centralised data review

EMA CTR536/2014

Article 48 · Monitoring

Article 48(2) is the legal basis for risk-based monitoring. Sponsor monitoring proportionate to risk. Reflection paper on RBM 2013 still operational. RMS assessment governed by Articles 5–8.

Acceptance criteriaRisk-proportionate · documented plan

PMDA J-GCPMHLW 28/1997

2024 RBM alignment

§21-22 monitoring. 2024 PMDA guidance accepts centralised-only monitoring for low-risk endpoints, aligning with E6(R3).

Acceptance criteriaRBM accepted · 2024 alignment

CDSCO NDCT2019

On-site frequency to verify

Rules 22-23. On-site monitoring expectations should be verified for site initiation, interim monitoring, and close-out, alongside RBM plans — in addition to RBM. Triggered escalation.

Acceptance criteriaOn-site at SIV/IM/COV minimum

MHRA UK CTRSI 2004/1031

RBM-aligned · GCP IT

UK MHRA GCP Inspectorate published RBM expectations 2014; updated 2023. Aligned with E6(R3).

Acceptance criteriaRBM · centralised data review

Health CanadaDivision 5

FDR C.05.010(c)

Sponsor responsibility for trial conduct. ICH-aligned. RBM principles recognised; Health Canada / HPFB implementation status should be checked against current guidance.

Acceptance criteriaRBM · ICH-aligned

Inspector's eye

For India-bound trials, moving fully to centralised or remote monitoring should be checked carefully against current CDSCO expectations and site-risk logic. For EU CTR trials, the documented critical-to-quality factor list remains a practical inspection-readiness surface.

/ 1.5 Data integrity. ★ALCOA+ · 21 CFR Part 11 · EU Annex 11 · PIC/S PI 041-1 · deepest divergence. +

At a glance · convergence vs divergence · the deepest pillar

CONVERGE

All recognise ALCOA+ (Attributable, Legible, Contemporaneous, Original, Accurate · plus Complete, Consistent, Enduring, Available). Audit trails are expected for computerised systems holding GCP records where applicable.

DIVERGE

21 CFR Part 11 (US, since 1997) and EU Annex 11 (Volume 4 of EudraLex) take different approaches to electronic-signature validation; MHRA Data Integrity Guidance Mar 2018 is a widely used inspectorate reference; PIC/S PI 041-1 consolidates the inspectorate position. Japan-bound programmes may still encounter institution-specific paper or signature workflows; current PMDA/J-GCP and ER/ES expectations should be verified. CDSCO data-integrity expectations follow PIC/S; eCRF-only assumptions should be checked carefully for Indian-only studies.

ICH E6(R3)2025-01-06

Principle viii · reliable results

Reliable trial results principle. ALCOA+ as data quality reference; cross-references E2A/E2B(R3), Q9(R1) quality risk management, M11 protocol structure.

Acceptance criteriaALCOA+ · audit trail integrity

FDA21 CFR Part 11

eRecords + eSignatures

21 CFR Part 11 (1997). eSignature = handwritten signature equivalent. Data Integrity Guidance Dec 2018. eSource Sep 2013.

Acceptance criteriaPart 11 · eSig validation

EMA CTREU Annex 11

EudraLex Vol 4 Annex 11

EU Annex 11 Computerised Systems. EMA Notice to Sponsors 2010 + Reflection Paper EMA/INS/GCP/454280/2010 on eSource and EHRs.

Acceptance criteriaAnnex 11 · CSV proportionate

PMDA J-GCPMHLW 28/1997

Print + sign legacy

Japan-bound programmes may encounter institution-specific paper or signature workflows; current PMDA/J-GCP and ER/ES expectations should be verified.

Acceptance criteriaPrint + sign legacy → relaxing

CDSCO NDCT2019

PIC/S-aligned

Schedule III data-integrity expectations follow PIC/S PI 041-1 in practice. eCRF acceptable; institutional ethics committees often still require paper printout.

Acceptance criteriaPIC/S aligned · paper still common

MHRA UK CTR2018 / 2023

★ Widely used DI reference

MHRA GxP Data Integrity Guidance Mar 2018. A widely used data-integrity guidance reference. Dynamic data, true copies, audit trail review at intervals.

Acceptance criteriaAudit-trail review at defined intervals

Health CanadaDivision 5

Canadian Food and Drug Regulations records

Canadian clinical-trial records retention should be verified against current Food and Drug Regulations requirements. Aligned to ICH E6 + PIC/S PI 041-1 in HPFB inspections.

Acceptance criteria25-yr retention · PIC/S alignment

Inspector's eye

Audit-trail review at defined, documented intervals remains a recurring data-integrity inspection theme in EU and UK settings. For Japan-bound trials, plan for paper-printout-and-signature workflows at older institutions even where the eCRF is fully validated. For US Part 11 systems, the eSignature meaning component is the most-frequent validation gap.

/ 1.6 Safety reporting.SAE / SUSAR · 7-day fatal/life-threatening · 15-day other · E2A/E2B(R3). +

At a glance · convergence vs divergence

CONVERGE

All adopt ICH E2A definitions (SAE, SAR, SUSAR, ADR). All use E2B(R3) electronic submission format. Sponsor expedited reporting timelines: 7 calendar days for fatal or life-threatening SUSARs, 15 calendar days for other SUSARs.

DIVERGE

EU CTR Article 41-43 centralises SUSAR submission via EudraVigilance Clinical Trial Module; FDA uses FAERS + IND Safety Reports per 21 CFR 312.32; PMDA uses JADER + PMDA-direct expedited reports; CDSCO Form CT-08 is India-specific; development safety reporting expectations often use DSUR/E2F concepts, but timing and route vary by jurisdiction and trial type.

ICH E6(R3)2025-01-06

Annex 1 §3.13 · cross-ref E2A/E2B/E2F

Cross-reference to ICH E2A definitions, E2B(R3) ICSR format, E2F DSUR. SUSARs to regulator and ethics; sponsor maintains overall safety profile.

Acceptance criteriaexpedited safety reporting · annual DSUR

FDA21 CFR 312.32

IND Safety Report

312.32 IND Safety Reports. Final Rule 2010 narrowed to suspected ADR by sponsor assessment. expedited reporting timelines apply where criteria are met. FAERS post-marketing.

Acceptance criteriaIND Safety Report expedited safety timeline

EMA CTR536/2014

Article 41-43 · EudraVigilance

CTR Article 41-43. EudraVigilance Clinical Trial Module (EVCTM) the single submission point for SUSARs in EU.

Acceptance criteriaEudraVigilance CTM · 7/15

PMDA J-GCPPAL Article 80-2

JADER + direct

Pharmaceuticals and Medical Devices Act §80-2. JADER post-marketing; PMDA direct expedited reports for clinical trials. expedited reporting timelines apply where criteria are met.

Acceptance criteriaPMDA direct · JADER

CDSCO NDCT2019

Form CT-08 SUSAR

Rules 27-30. Form CT-08 expedited safety report. SUSARs to CDSCO and Ethics Committee. Compulsory compensation for CT-related injury (Rule 39).

Acceptance criteriaForm CT-08 · expedited safety timeline

MHRA UK CTRSI 2004/1031

SUSAR via MHRA portal

Schedule 1 Part 5. Post-Brexit MHRA portal for SUSARs (no longer EudraVigilance). expedited reporting timelines apply where criteria are met. Annual Safety Report (DSUR) due 60 days after development international birth date.

Acceptance criteriaMHRA portal · DSUR DIBD+60

Health CanadaDivision 5

FDR C.05.014

FDR C.05.014 reporting of serious unexpected ADRs. expedited reporting timelines apply where criteria are met. Canada Vigilance database; ICH E2A/E2B aligned.

Acceptance criteriaexpedited safety timeline · Canada Vigilance

/ 1.7 TMF · Reference Model 3.3.Trial Master File · paper or electronic · inspection-ready throughout. +

At a glance · convergence vs divergence

CONVERGE

All require TMF · sponsor and investigator portions distinct · inspection-ready throughout study, not at study end. DIA TMF Reference Model 3.3 (2022) the de-facto industry standard structure.

DIVERGE

EMA Reflection Paper on TMF (2018) sets the most explicit timing expectations: documents in TMF within agreed timeframes proportionate to risk. FDA guidance silent on TMF as a structure — 21 CFR 312.62 / 812.140 records-and-reports requirement is what the TMF satisfies. PMDA has institution-level Investigator Site File (ISF) expectations that pre-date the DIA Reference Model. Retention varies: retention periods and triggers should be verified by jurisdiction, product type, and trial status.

ICH E6(R3)2025-01-06

Annex 1 §3.16 · principle xi

TMF as quality system component. Sponsor TMF + Investigator Site File. Inspection-ready throughout. ICH E6(R3) deletes the prescriptive document list of R2 · principle-based.

Acceptance criteriaInspection-ready · principle-based

FDA21 CFR 312.62

Records-and-reports

312.62 sponsor + investigator records. No TMF as structure · the records-and-reports requirement is what TMF satisfies. 2-year retention post-marketing or post-IND withdrawal.

Acceptance criteria2-yr retention post-marketing

EMA CTR536/2014

Article 57-58 · 25-yr

CTR Article 57 sponsor TMF + Article 58 investigator TMF. 25 years archive. EMA Reflection Paper on TMF 2018.

Acceptance criteria25-yr archive · sponsor + invest TMF

PMDA J-GCPMHLW 28/1997

ISF institution-level

§36 essential records. Investigator Site File at institution level pre-dates DIA Reference Model. Retention 3 years post-end of study or 5 years post-approval, whichever later.

Acceptance criteria3-5 yr · ISF institution-level

CDSCO NDCT2019

Rule 24 · 5-yr

Rule 24 records retention 5 years post-completion or post-discontinuation. Investigator File + Sponsor File. Form CT-09 progress reports retained.

Acceptance criteria5-yr retention

MHRA UK CTRSI 2004/1031

25-yr post-Brexit

Schedule 1 Part 7. Aligned with EU CTR 25-year retention. MHRA GCP Inspectorate uses TMF Reference Model 3.3 in practice.

Acceptance criteria25-yr retention · TMF RM 3.3

Health CanadaDivision 5

Canadian Food and Drug Regulations · 25-yr

Canadian Food and Drug Regulations records retention 25 years. ICH E6 + DIA TMF RM 3.3 in practice.

Acceptance criteria25-yr retention · ICH-aligned

Inspector's eye

eTMF completeness at inspection — not retrospectively rebuilt on the eve of audit — is the single most-flagged finding across MHRA, FDA BIMO, and EU CTR inspections. The DIA TMF Reference Model 3.3 zone structure (Trial Management, Central Trial Documents, Regulatory, IRB/IEC, Site Management, Investigational Product, Safety Reporting, Statistics, Data Management, Third Parties, IP & CRO oversight) is what every modern eTMF tool ships with.

/ 1.8 Source documentation.Source data → CRF traceability · certified copies · eSource · EHR-to-EDC. +

At a glance · convergence vs divergence

CONVERGE

The compared frameworks require source documentation that is contemporaneous, attributable, traceable to the CRF entry. Certified-copy concept recognised. eSource can be acceptable when protocol definition, controls, and local expectations support it.

DIVERGE

FDA eSource Sep 2013 is the foundational guidance — eCRF as source data permitted with adequate protocol justification; EMA Reflection Paper EMA/INS/GCP/454280/2010 + 2024 update covers EHR-to-EDC. PMDA expectations can require explicit identification of source vs CRF in protocol; mismatched expectations remain frequent in non-Japanese sponsors. CDSCO ethics committees may request paper source even where eSource is protocol-defined.

ICH E6(R3)2025-01-06

Annex 1 §3.15 · ALCOA+

Source data identified in protocol. ALCOA+. Direct access to source for monitor, auditor, regulator. Certified copies recognised.

Acceptance criteriaSource identified in protocol · ALCOA+

FDA2013 / 2024

eSource Guidance

Electronic Source Data in Clinical Investigations Sep 2013. eCRF as source allowed with protocol justification. EHR-to-EDC consistent with this.

Acceptance criteriaeCRF-as-source · protocol justification

EMA CTR2010 / 2024

EMA/INS/GCP/454280/2010

Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials. Updated 2024 for EHR.

Acceptance criteriaEHR-to-EDC · EMA reflection paper

PMDA J-GCPMHLW 28/1997

Source list in protocol

§47 case report form. Explicit identification of source vs CRF in protocol. Mismatched expectations remain frequent for first-time-in-Japan sponsors.

Acceptance criteriaSource-vs-CRF list in protocol

CDSCO NDCT2019

EC paper-source ask

Rules 22-23 monitoring and Schedule III context should be checked; Ethics Committees may request paper source even where eSource is protocol-defined.

Acceptance criteriaPaper source still common at EC level

MHRA UK CTR2018 / 2023

DI Guidance + GCP

MHRA Data Integrity Guidance Mar 2018 covers source data. eSource accepted; EHR-to-EDC accepted with risk assessment.

Acceptance criteriaeSource · risk assessment for EHR

Health CanadaDivision 5

ICH-aligned

Canadian Food and Drug Regulations records. ICH-aligned. eSource accepted; HPFB inspections expect protocol-level identification.

Acceptance criteriaICH-aligned · protocol identification

/ SRC

Official source register.

GCP / trial conduct anchors

ICH E6(R3)

Good Clinical Practice Step 4.

Official ICH E6(R3) Step 4 guideline. Use as the primary GCP anchor for participant protection, quality-by-design, sponsor oversight, and proportionality.

PDF ↗

ICH E8(R1)

General considerations for clinical studies.

Official ICH E8(R1) guideline. Use for quality-by-design and critical-to-quality thinking before trial execution begins.

PDF ↗

ICH E9(R1)

Estimands and sensitivity analysis.

Official ICH E9(R1) addendum. Use for aligning trial objectives, intercurrent events, estimands, and statistical interpretation.

PDF ↗

ICH M11

Clinical electronic structured harmonised protocol.

Official FDA-hosted ICH M11 page. Use for structured protocol thinking and protocol information that can become more reusable across systems.

official ↗

FDA DCT

Clinical trials with decentralized elements.

FDA guidance page for decentralized trial elements. Use for remote visits, local healthcare providers, direct-to-participant processes, and oversight expectations.

official ↗

FDA DAP