ICH E6(R3) vs E6(R2): what changed in Good Clinical Practice

What changed

R2 says GCP applies to "clinical trial data intended for regulatory submission" and broadly to "other clinical investigations that may affect human subject safety and well-being"; R3 says it "applies to interventional clinical trials of investigational products intended to be submitted to regulatory authorities" and that the Principles "may be applicable to other interventional clinical trials ... not intended to support marketing authorisation applications". R2 states detailed, prescriptive obligations in the main text (for example, specific monitoring/audit/quality definitions, detailed sponsor/investigator/IRB responsibilities, and retained-document periods), while R3 says "Annex 1 and its appendices provide the basis for interpretation and application of the principles" and emphasizes principles-based, risk-proportionate application instead of repeating those same detailed operational obligations in the provided text. R3 adds items not stated in the R2 text here, including that quality should be built in as "fitness for purpose," that factors critical to quality should be identified prospectively, that serious noncompliance should be avoided/detected/addressed/prevented from recurring, that processes should be proportionate to risks and the importance of data while avoiding unnecessary burden, and that trials should have timely public registration and public posting of results.

What changed

Compared with the baseline wording that the IRB/IEC "should have a reasonable number of members" and review specified documents before trial start, R3 broadens and reframes the same oversight in several places: it says the IRB/IEC "may be institutional, regional, national or supranational" and that submissions/communications "may in many regions be combined with submissions to regulatory authorities" and "may be made by the investigator/institution or by the sponsor"; it adds assent materials and assent review for minors; it adds that alternative expedited processes may apply where allowed; it requires prompt reporting of deviations, changes that increase risk, and "new information that may adversely affect participant safety or trial conduct"; and it describes documented procedures for "appeal procedures". These are additions/rewordings relative to R2 rather than a removal of the core IRB/IEC obligations, but they still change the documented rule set.

What changed

R2 baseline: the protocol is to identify "the investigator or investigators responsible for conducting the trial," "the trial site addresses and telephone numbers," "any qualified physician or dentist responsible for all trial-site related medical or dental decisions if that person is not the investigator," and "the clinical laboratories, medical or technical departments, and institutions involved in the trial." R3 Appendix B instead requires "the name and address of the sponsor and the name and title of the person or persons authorised to sign the protocol and protocol amendments for the sponsor," and says investigator-side responsibilities are established elsewhere: "the investigator/institution should sign the protocol or an alternative contract to confirm agreement with the sponsor," and protocol or agreement should specify access/inspection permissions. R2 also says the protocol "usually also gives the background and rationale for the trial" and may place some of that in other protocol-referenced documents; R3 retains that but adds that the protocol should be "clear, concise and operationally feasible" and designed to "minimise unnecessary complexity" and "mitigate or eliminate important risks."

What changed

Compared with the baseline, R3 adds or makes explicit: "trial objectives and purpose" plus "estimands when defined"; broader design examples and "operationally feasible"/"quality-by-design" framing; "placebos and comparators" and "maintenance of treatment randomisation codes and code-breaking procedures"; a requirement to specify "the mechanism for pre-screening and screening"; explicit handling of "dose adjustment or dose interruption"; endpoint committee procedures and that committees should typically be blinded; statistical criteria for stopping the trial; for Bayesian design, "the threshold for success on the posterior probability"; explicit "procedures for handling intercurrent events" aligned with estimands; development of a separate SAP unless the protocol suffices; predefined analysis-set criteria in protocol or SAP; and detailed unblinding documentation/safeguards in data handling. Baseline R2 already covered primary/secondary endpoints, efficacy/safety parameters, methods/timing of assessments, planned interim analyses, sample size/power, level of significance, selection of subjects for analyses, randomization, blinding, and code-breaking procedures, but it did not expressly include these R3 additions or refinements in the text provided.

What changed

Compared with R2’s baseline wording, R3 adds or makes explicit: "subject inclusion criteria and subject exclusion criteria" -> "participant inclusion criteria, exclusion criteria, and any pre-screening or screening mechanism"; treatment detail expands from "investigational treatment in operational detail" with permitted/not permitted medications and compliance monitoring to explicit "criteria for dose adjustments," "dose adjustment or dose interruption rules," "schedule of events," and decentralized/shipping-at-participant-location administration; discontinuation expands from protocol "subject withdrawal criteria" and procedures for "withdrawing subjects from the trial or investigational product treatment" to explicit separation of "discontinuation of trial intervention and withdrawal from the trial," consent information about voluntary stopping "at any time without penalty or loss of benefits," reasons/circumstances for termination, and how data will be handled after stopping/withdrawal/discontinuation; safety oversight also broadens from sponsor safety evaluation and possible DMC recommendation to continue/modify/stop to more explicit risk-management, recruitment/retention review, and participant-protection framing.

What changed

E6(R2): "efficacy assessment is to be specified through the efficacy parameters and through the methods and timing for assessing, recording, and analysing those parameters"; "safety assessment is likewise to be specified through the safety parameters and the methods and timing for assessing, recording, and analysing them, together with procedures for eliciting reports of adverse events and intercurrent illnesses and the type and duration of follow-up after adverse events." E6(R3): "efficacy assessment is addressed in Appendix B.8 through specification of efficacy parameters and the methods and timing for assessing, recording and analysing them" and "Safety assessment is addressed in Appendix B.9 through specification of safety parameters; the methods, extent and timing for recording and assessing them; procedures for obtaining, recording and reporting adverse events; and the type and duration of participant follow-up after adverse events and other events such as pregnancies." R3 also adds that if committees are used for assessing efficacy or safety data, their procedures, timing and activities are to be described, and that the sponsor is responsible for "ongoing safety evaluation" and safety reporting using the Investigator's Brochure or other current scientific information as the basis.

What changed

Baseline R2 says: "protocol must also specify direct access arrangements: the sponsor should ensure that the protocol or another written agreement states that the investigator or institution will permit monitoring, audits, IRB/IEC review, and regulatory inspections with direct access to source data and source documents"; R3 says: "direct access is expressly defined as permission to examine, analyse and verify important trial records, on-site or remotely, and the sponsor must ensure protocol or agreement language requiring investigator/institution direct access to source records for monitoring, audit, inspection and, where applicable, IRB/IEC review, with participant consent for that access and confidentiality protections for identities, personal data, and sponsor proprietary information." Baseline R2 says source data are original records and certified copies of original records, and source documents are the original documents, data, and records in which those source data reside; R3 says source records are original documents or data, including relevant metadata, or certified copies, and the investigator must define what counts as source records, how data are captured, and where source records are located. Baseline R2 centers on CRFs and essential documents and requires changes to CRFs to be dated, initialed, and explained if necessary; R3 adds data acquisition tools, metadata, trial master file/investigator site file, full data life-cycle controls, and audit trails as metadata records, plus requirements for timely investigator access to protocol-collected and some external-source data and for protection of computerised systems and participant privacy across digital workflows. R3 also adds explicit retention/archiving rules for trial data and metadata and allows permanent destruction when no longer required, whereas R2 focuses on retaining essential documents until the stated post-development period and on making requested trial-related records available on request.

What changed

ICH E6(R2): GCP is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials, intended to assure that data/results are credible and accurate and that subjects’ rights, safety, well-being, integrity, and confidentiality are protected; quality management is tied to assuring every aspect of the trial and risk-based monitoring, QA/QC, and oversight of trials, with no explicit quality-by-design definition, no explicit critical-to-quality-factor framework, and no explicit data-governance/transparency provisions. ICH E6(R3): GCP is a standard for planning, initiating, performing, recording, oversight, evaluation, analysis and reporting of clinical trials that assures trial data/results are reliable and participants’ rights, safety and well-being are protected; it explicitly defines quality as fitness for purpose, requires identification of factors critical to quality, states quality by design, and adds explicit risk-based quality management across the lifecycle, broader data life-cycle governance, fit-for-purpose computerised systems, transparency (registration/results posting), and more detailed provisions for decentralized/digital practices and roles/oversight.

What changed

R2 says the protocol should include financing and insurance if not addressed in a separate agreement, and publication policy if not addressed in a separate agreement; R3 also places these in Appendix B/protocol architecture and adds broader documented agreements with service providers and other parties plus public registration/public posting of trial results and sponsor provision of results. R2 requires an insurance statement where applicable and financial aspects documented in an agreement; R3 keeps that and adds essential-record language for "arrangements between parties on the financial aspects of the trial" and "insurance/indemnity arrangements."

What changed

Compared with the baseline ICH E6(R2), ICH E6(R3) is not a direct one-to-one restatement: R2 says the sponsor should "implement a system to manage quality throughout all stages of the trial process" and uses specific provisions on QA/QC, monitoring, and computerized systems; R3 keeps that overall obligation but reframes it as an integrated quality-management and risk-management system "throughout all stages of the trial process," adds explicit ongoing identification of risks "before trial initiation and throughout trial conduct," adds broader data-governance requirements (including metadata review/retention, data life cycle controls, and blinding safeguards), and introduces more explicit duties for investigators, institutions, service providers, and developers. Nothing in the provided R3 text shows a loss of the baseline's core R2 obligations; rather, the baseline obligations are kept and expanded/reworded/moved into the new structure.

What changed

Compared with the baseline, R3 is not identical in presentation but is substantively compatible overall on this subject: R2 says the sponsor is responsible for the initiation, management, and/or financing of a clinical trial and that transferred duties remain with the sponsor; R3 says the sponsor is responsible for the initiation, management and arrangement of trial financing and that transferred activities to service providers do not remove ultimate responsibility. R2 requires duties/functions transferred to a CRO to be specified in writing; R3 requires activities transferred to service providers to be specified in an agreement, with additional language on documented allocation of responsibilities in multi-sponsor trials. R2 requires before trial initiation that the sponsor define, establish, and allocate all trial-related duties and functions; R3 rephrases this as determining roles and allocating activities before initiating trial activities. R2 emphasizes monitoring, QA/QC, and essential documents; R3 moves much of this into a broader essential-records framework and adds explicit risk-proportionate oversight, fit-for-purpose quality, and service-provider oversight. R2 ties safety reporting to expedited reporting of serious unexpected ADRs and periodic safety reports; R3 frames safety mainly through sponsor safety assessment/reporting, monitoring of AE reporting timeliness, and essential records for SAE/SUSAR notifications. R2 lists investigational product labels, handling instructions, shipping records, certificates of analysis, decoding procedures, a master randomization list, and trial initiation monitoring reports as essential documents; R3 retains analogous investigational-product and records content but under essential records, with updated terminology such as packaging, relabelling, destruction records, emergency decoding procedures, and traceability from manufacturer release through disposition.

What changed

R2 says the sponsor should use on-site monitoring, centralized monitoring, or both where justified, and document the rationale in a monitoring plan; R3 says the monitoring approach must consider decentralised settings, be tailored to potential safety/data-quality/result-reliability risks, and cover activities and services outside investigator sites such as central laboratories and central image reading facilities. R2 defines centralized monitoring as remote and timely evaluation of accumulating data by appropriately qualified and trained persons, and allows central monitoring to complement or reduce on-site monitoring; R3 adds remote and secure direct read-only access to source records, data acquisition tools and essential record retention systems, and says site monitoring frequency is adjusted using knowledge gained during the trial. R2 frames audit as sponsor QA independent of routine monitoring and QC, with audit reports/certificates and procedures based on trial importance, size, type, complexity, subject risk and identified problems; R3 keeps that but adds that audits may be on-site and/or remote, and states the audit should be proportionate to trial-conduct risk. For multicentre trials, R2 focuses on sponsor organization/selection of coordinating committee or coordinating investigator and documented responsibilities before trial start; R3 retains that, but adds oversight/communication arrangements across parties involved in trial conduct, including centrally performed activities, and mentions possible signatory status in the trial report for a coordinating investigator.

What changed

Compared with the R2 baseline, R3 is compatible on the core concepts that the protocol is the controlled design document, amendments are formally documented, and IRB/IEC approval is required before trial initiation. The material departures are: R2 says the protocol must be followed in "strict compliance" and requires "signed protocol and amendments, if any" on file before start; R3 instead says the trial should be conducted in compliance with the approved protocol and requires documented and dated IRB/IEC approval or favourable opinion, but the evidence given does not repeat the R2 signed-on-file requirement. R2 frames amendment control around "changes to the protocol" and ongoing filing/monitoring of approved amendments; R3 reframes this as documented protocol amendments under a quality-by-design and risk-proportionate approach, adds that protocol development may include predefined adaptability to reduce deviations or the need for an amendment, and permits some changes without prior IRB/IEC approval when necessary to eliminate immediate hazards or when they are only logistical or administrative. R3 also adds explicit planning elements not stated in the R2 evidence here: protocol-execution documents such as the statistical analysis plan, data management plan, and monitoring plan, plus critical-to-quality factors and mitigation strategies.

What changed

R2 says the investigator should maintain "a list of appropriately qualified persons to whom significant trial-related duties have been delegated" and is responsible for supervising those to whom "trial-related duties and functions" are delegated; R3 expands this to say tasks, duties or functions may be transferred by the sponsor or delegated by the investigator, each retains overall responsibility, and the investigator may delegate "trial-related activities" to other persons or parties, including service providers, while maintaining proportionate oversight and a record of persons/parties, with "documentation of delegation of trial-related activities, signature documentation, and trial-specific training records" as essential records. R2 frames site suitability as the investigator having "adequate resources" and monitors verifying qualifications/resources during the trial; R3 keeps that but adds sponsor responsibility to ensure sufficient resources are available and makes site selection/initiation monitoring explicitly confirm investigator site staff, laboratories, equipment and other facilities are adequate.

What changed

ICH E6(R3) changes, adds, and in some places refines the baseline obligations. Compared with R2’s wording that consent is documented by a "written, signed, and dated informed consent form" and that the investigator/institution must obtain it before participation, R3 allows the form to be "paper or electronic," explicitly permits remote consent where appropriate, and requires identity verification for in-person or remote consent. R2 requires the subject or legally acceptable representative to be informed "of all pertinent aspects of the trial" and gives a fixed list of consent content; R3 keeps the same core disclosures but adds explicit discussion of "follow-up procedures after stopping treatment, withdrawal, or discontinuation," "how participant data will be handled including after withdrawal or discontinuation," "availability of trial results," and "actual treatment information if desired once available from the sponsor." R2 says the participant or representative must be fully informed and that new information relevant to willingness to continue must be communicated; R3 adds that participants must be given the opportunity to discuss all relevant aspects, that new information must be assessed for whether re-consent is needed, and that the communication and confirmation of willingness to continue must be documented. R2’s IRB/IEC role is to ensure protection of rights, safety, and well-being and review protocol, consent forms, recruitment, safety information, and compensation; R3 retains that role but explicitly broadens review to assent materials, the consent/assent process, participant-facing media, emergency-trial ethics concerns, and payment timing/method to avoid coercion. R2 speaks in terms of direct access to original medical records by monitors, auditors, IRB/IEC, and regulators; R3 restates this as direct access to source records by regulatory authorities, sponsor representatives, and, where applicable, IRBs/IECs. R2 is silent on assent as a general consent feature beyond special populations, while R3 expressly requires assent for minors as appropriate and for capable participants in representative-consent populations. R2 contains no general statements about use of images, videos, interactive methods, telephone, or video conferencing, while R3 expressly permits varied and remote methods and notes paper alternatives may be offered.

What changed

Compared with the baseline, R3 retains the same core duties to keep source data/trial records, report SAEs/SUSARs, submit status reports, and handle suspension/termination/closure, but it changes the framing and scope in several places: baseline says the investigator/institution must maintain “adequate and accurate source documents and trial records” and “essential documents” protected from premature destruction, while R3 requires “adequate source records,” defines them as part of “essential records,” and adds “data acquisition tools,” metadata, audit trails, version control, and broader data-integrity/security requirements. Baseline says investigators submit “written summaries of trial status to the IRB/IEC annually, or more frequently if requested,” while R3 says “documented summaries of trial status… in accordance with local regulatory requirements or on request,” and lists interim or annual reports and final reports as essential records. Baseline requires the sponsor to ensure clinical trial/study reports are prepared and provided to regulators as required; R3 keeps that but also adds that after unblinding and finalization the sponsor should generally make trial results publicly available and provide results/treatment information to investigators and participants as applicable.

What changed

Compared with R2’s baseline, R3 adds and/or tightens: R2 says the IB is for "clinical and nonclinical data... relevant to their study in human subjects" and supports protocol rationale/compliance and clinical management; R3 says it is for "human participants," adds that it "forms, together with applicable alternative product information where permitted, the basis of safety assessment and reporting," and explicitly mentions investigator site staff. R2 allows a "basic product information brochure, package leaflet, or labelling" to substitute where permitted; R3 narrows this to "current scientific information such as a basic product information brochure, for example a summary of product characteristics, package leaflet or labelling" and adds that for a new indication an IB specific to that use should be prepared "unless there is a rationale for having only one IB." R2 says the IB "should be reviewed at least annually and revised as necessary"; R3 keeps that but adds that the sponsor must ensure it is updated as significant new information becomes available and that safety updates and periodic reports may include changes. R2’s title page only "suggest[s]" edition/reference to superseded edition; R3 adds "data cut-off date" and may include a signature page. R2’s confidentiality statement is limited to the investigator’s team and IRB/IEC; R3 extends the audience to investigator site staff and regulatory authorities. R2 says the body should contain a summary, introduction, physical/chemical/pharmaceutical properties, nonclinical studies, effects in humans, and summary of data and guidance; R3 keeps these but says literature references go at the end of each chapter where appropriate. In nonclinical content, R2 names toxicology subheadings including "special studies such as irritancy and sensitisation, reproductive toxicity, and genotoxicity or mutagenicity"; R3 restates the structure as "single and repeated dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, local tolerance and other toxicity studies where appropriate." In human data, R2 requires summarizing completed clinical trials and marketing experience; R3 also asks for ongoing trials with available interim results that may inform safety evaluation. R2 says investigators are responsible for providing the up-to-date IB to the IRB/IEC; R3 instead says a current copy should be provided to the IRB/IEC before trial initiation and updated during the trial, and also says investigators should be familiar with the IB, product information, and other sponsor-provided sources. R2 defines unexpected ADRs against the IB as an example of applicable product information; R3 adds explicit reference safety information (RSI) for SUSAR reporting, requires a cumulative list of expected ADRs in the RSI, and says unexpectedness may be judged against the IB or alternative documents.

ICH E6(R2) requires the Investigator’s Brochure to include investigational product identity, physical/chemical/pharmaceutical properties, and formulation details as mandatory content. ICH E6(R3) retains these requirements but reorganizes them, adds the option for a current basic product information brochure for authorised medicinal products when permitted, and expands related sponsor-control language around annual review and updated product-information governance.

What changed

Compared with R2’s focus on the IB as a compilation of clinical and nonclinical data used to inform investigators, R3 adds broader trial-use framing: "the nonclinical evidence in the IB also feeds into later IB interpretation and trial safety use," including that "the Summary of Data and Guidance" should aid interpretation of available data, and that the IB "forms the basis of safety assessment and reporting for the trial" with reference safety information used for expedited SUSAR expectedness. R2 does not state these later safety-reporting roles. R3 also says the IB is for human "participants" and that the summary should "briefly" highlight information, while R2 says "subjects" and does not use the "briefly" qualifier. In the toxicology outline, R3 lists "local tolerance" and "other toxicity studies" and uses "single toxicity" / "reproductive and developmental toxicity," whereas R2 lists "special studies such as irritancy and sensitisation" and "reproductive toxicity" / "genotoxicity or mutagenicity."

What changed

R2: “Where possible, a summary of each completed clinical trial should be provided” and no reference to ongoing trials or reference safety information. R3: “Where possible, it should summarise each completed clinical trial and any ongoing trials for which interim results are available if those results may inform safety evaluation”; “The brochure contains the reference safety information... for expedited reporting of suspected unexpected serious adverse reactions”; “adverse drug reactions suspected to be product-related with a high level of certainty should be included in the reference safety information and/or the investigator’s brochure.”

What changed

Baseline R2: "essential documents" are a defined set with a minimum list grouped into before/during/after trial, TMFs are established at the beginning of the trial at both the investigator/institution site and the sponsor site, and the sponsor/investigator institution maintain records of the location of their respective essential documents, including source documents. R3: the subject is framed as "essential records" rather than "essential documents"; records may be "documents and data, including relevant metadata and in any format"; the TMF is no longer treated only as a single sponsor archive but as repositories held by both parties, with the investigator/institution repository also referred to as the ISF; record scope is based on criteria and an expressly non-exhaustive table rather than the R2 minimum list; records may be retained by one party, both, or outside trial-specific repositories; storage requires traceability of authors/reviewers/approvers and metadata-certified copies; and R3 adds explicit service-provider, computerised-system, and data-governance controls that are not stated in the R2 text shown here.

What changed

Compared with R2’s pre-trial essential documents list, R3 retains core items such as the Investigator’s Brochure/basic product information brochure, signed protocol, IRB/IEC approval, regulatory authorisation where required, financial arrangements, insurance, agreements, investigator qualifications, normal values/ranges, handling instructions, shipping records, certificates of analysis, decoding/randomisation materials, and site monitoring reports. R3 also adds or expands pre-start records that R2 did not list in this section: sample data acquisition tools (including diaries and clinical outcome assessments), translated participant information, documentation of selection/assessment/oversight of service providers, trial-specific training records, delegation records, signature sheets, instructions for important trial-specific systems such as IRT or eCRF manuals, equipment fitness records, trial-specific computerised system validation and fitness-for-purpose documentation, statistical planning records, and IDMC/adjudication committee materials. R2’s “pre-trial essential documents” framing is replaced by R3’s broader “essential records” framework and “should generally be in place prior to the start of the trial” wording.

What changed

R2: "essential documents" during trial conduct, with a defined table of required records and filing locations; R3: "essential records" for records before and during trial conduct, including "documents, data and relevant metadata," with records "not exhaustive" and selected by "risk-proportionate approaches". R2: TMFs are to be established at the beginning of the trial at both the investigator/institution site and the sponsor site; R3: records may be maintained in or referred to from repositories held by the sponsor and investigator/institution, which may be referred to as the TMF and ISF. R2: during-trial documents are listed as required items; R3: the Essential Records Table adds new categories such as data-management/statistical-analysis plans, computerised system validation, service-provider oversight, IDMC/adjudication materials, and records relating to security breaches, unblinding, and digital/system traceability that have no corresponding R2 requirement in the evidence shown.

What changed

R2 says post-trial essentials are "all documents previously identified for the trial in Sections 8.2 and 8.3, kept together with a specific set of close-out documents listed in Section 8.4" and explicitly names items like "a final trial close-out monitoring report," "the final report by the investigator to the IRB/IEC," and "the clinical study report." R3 instead says it "does not create a separate close-out bundle consisting only of end-of-trial papers" and that at the end of the trial parties retain "their essential records"; Appendix C lists examples including "site monitoring reports including close-out reports," "the final report to the IRB/IEC and regulatory authorities where required," and "interim and final clinical trial reports."

ICH E6(R2) and ICH E6(R3) both cover investigational product management plus randomisation/blinding as protocol-controlled GCP functions. R3 keeps the core obligations but expands them with more explicit sponsor-side monitoring, direct-to-participant / decentralized supply options, and additional safeguards for unblinding and blinding maintenance.

What changed

Compared with R2’s baseline scope, R3 adds or broadens defined terms and operational concepts for modern trial conduct: it explicitly defines service provider, data acquisition tools, metadata, relevant metadata, and a fuller audit trail concept; it expands source records to include electronic and automated-origin data such as ePROs, wearables, sensors, EHR and laboratory systems; it introduces trial-design examples including adaptive, platform/umbrella/basket, and decentralized elements; and it strengthens protocol/data-governance content around critical-to-quality factors, risk-proportionate approaches, computerized-system validation, and safeguarding blinding. R3 also reframes safety terminology and reporting around reference safety information and current product information, and it allows broader modern consent, direct-access, and remote/decenralized practices. R2 has no corresponding standalone vocabulary for several of these modern trial-method concepts beyond limited electronic-record and centralized-monitoring references.

What changed

ICH E6(R2): "The guideline frames these topics primarily through sponsor responsibilities, protocol content, investigator recordkeeping, and monitoring and audit controls." ICH E6(R3): "establishes a risk-proportionate framework for clinical trial data management, computerised systems, statistical analysis, records retention and reporting across the full trial data life cycle" and adds explicit requirements for "data acquisition tools," "relevant metadata," "audit trails," "statistical programming," "essential records," and that the sponsor should "generally make trial results publicly available" after unblinding and finalisation.