The International Council for Harmonisation’s (ICH) E6 Good Clinical Practice (GCP) guideline is now updated to revision three (R3) and has reached Step 2b where it is now available for public consultation. What does this mean? Well, it means that the ICH Expert Working Group for ICH E6(R3) (EWG) has been updating the ICH E6(R2) GCP guideline (current version) and it is now available on the ICH website for you to go and leave your comments!

As the changes are not summarised or highlighted or put in separate added “addendums” as the previous time (R1 updated to R2), I decided to take it upon myself to review ICH E6(R2) and ICH E6(R3) and compare the changes that have been made. O boy! Was that a time-consuming task … it was quite a major update, or as I refer to it, a facelift!

Please be warned that this is a long read as it was an extensive update! I do hope that my summary will assist you in your own review of the ICH E6(R3) document and maybe support and encourage you to provide your comments via the ICH website.

The following information in this article is my summary of the changes that I have identified, I am in no capacity representing the EWG or their views.

My executive summary:

I got the overall impression that the revised version of ICH GCP E6 (namely R3) aims to enhance flexibility, relevance, and adaptability to various trial designs and methodologies, including the integration of new digital technology innovations like wearables and sensors.

Quality is emphasized right from the beginning of the trial design process. The guideline encourages input from a wide range of stakeholders, including participants and healthcare providers, to ensure that the protocol, informed consent, and data systems are meaningful, feasible, simple, practical, and manageable for the trial site.

Sponsor responsibilities and oversight are given increased importance in R3. Sponsors must now ensure they have trained and qualified staff and adequate resources to support the trial site. Safety oversight requires sponsors to include pauses for interim analysis, during which investigators endorse the collected data in stages. Sponsors are also required to provide investigators with information about selected vendors for investigator activities that cannot be conducted at the site, allowing investigators to decide if they are comfortable using them.

R3 introduces a dedicated section on Data Governance, emphasizing the importance of a simple and proportionate data management plan and monitoring plan based on risk analysis. The entire data lifecycle is emphasized, including data capture, correction, and the use of metadata (built-in flag systems) that are traceable and maintain an audit trail. Double steps for data verification are now required to ensure data quality.

ICH GCP E6 (R3) aims to modernize and align with scientific and technological advancements. While digital workflow solutions are beneficial for cross-functional collaboration, they must be “fit for purpose” to avoid unnecessary complexity. Inadequate design can waste resources and the time and efforts of investigators and participants.

The scope of ICH GCP remains focused on interventional clinical trials involving investigational products such as drugs, medicines, medicinal products, vaccines, and biological products. The revised guideline is now media-neutral, allowing for the use of different technologies for documentation, thereby promoting diversity in clinical trials and reaching a broader population.

My summary of changes:


The layout had a facelift! The glossary moved to the back. The guideline now includes annexes that tries to clarify how the principles can be applied in various types of trials and remain relevant. Clinical trials and the initial principles were applied to the paper industry. Now it must be applied to a very technological and methodological industry. A whole new section on “Data Governance” was added to Annex 1, section 4. This layout makes provision for additional annexes to be developed as the industry develops and stakeholders come up with new innovations in design and conduct.


  1. Introduction
  2. Principles
  3. ANNEX 1
    1. IRB
    3. SPONSOR



  1. Investigator Brochure
  2. Clinical Trial Protocol
  3. Essential records

Let’s investigate the sections one by one:


A key change is the reference made to the ICH E8 (R1) general considerations for clinical studies to emphasise designing quality into a clinical trial, identifying factors that are critical to trial quality, engaging stakeholders and using a proportionate risk-based approach. A key objective of the revision was to further embed the proportionate risk-based approach into the guideline.

The scope was made clear – the guideline remains focussed on those clinical trials intended to support applications to regulatory authorities, to reduce it to those trials of investigational medicinal products and according to local requirements. I believe the aim of this is to discourage the application of the guideline to other trials that do not involve medicinal products.

Principles – now section 1 not 2

The 13 principles of ICH GCP E6 (R2) are now combined into 11 principles on R3. They are designed to be flexible and applicable to a broader range of clinical trials. It aims to be considerate and plans to address even unique aspects of an individual clinical trial. Each principle is explained in depth  to assist in the understanding of how to implement it. . I prepared a summary sheet of how the R2 principles were incorporated into the 11 “new” principles which I will also make available as a quick reference guide.

IRB/IEC – Annex 1 section 1

There has been a small number of changes to the IRB/IEC section, although some are quite significant.

  1. The information to be reviewed by the IRB/IEC has been restructured to form a bulleted list and expanded to cover situations using innovative methods, such as electronic informed consent.
  2. The IRB may request more than the standard listed material to be provided to the participant or request extra information to be discussed with the participant about the study during consent if they feel this will assist in their understanding, protection and safety.
  3. It now specifically states that if minors are to be included in a trial the IRB/IEC should review the assent information – considering the maturity, age and psychological state of the minor.
  4. Compensation should be decided prorated/upfront – not based on completion – and the method, amount, schedule of payment must be discussed in the consent and reviewed by the IRB. There has been a change to state that the reimbursement of reasonable travel and lodging expenses to trial participants is not considered coercive.
  5. Depending on the region, it may be allowed to combine your submission and communication to regulatory authorities and IRB into one submission. GCP also recognizes that in some regions the submissions are done by the site and in others by the sponsor.
  6. This revision acknowledges the fact that there might be different requirements / regulations in different countries and therefore in some instances added the text “or as applicable to regulatory requirements” to make room for various regulations to be taken into account. For example, in relation to SUSAR reporting and the removal of the 3-year record retention requirement.

Investigator – Annex 1 – Section 2 not 4

There have been extensive changes to the investigator section, with significant deletions, additions, and restructuring, so I have quite a bit to cover in this section.


The PI must be able to prove that they can recruit the numbers (retrospective or current data)


  1. The sponsor may support the PI to identify a third party for delegation of trial-specific activities; however, it is the FINAL decision of the PI if they agree that the services of the 3rd party suggested by the sponsor is appropriate.
  2. The PI takes ultimate ensure these parties are delegated, qualified, trained, and informed (like home nurses arranged by the sponsor).
  3. Agreements with vendors must be documented.
  4. Another positive change in delegation of duties is that, should their clinical trial duties be part of their normal routine, they do not need to be delegated – I think this could encourage investigators and sponsors in that trial-specific training and delegation log completion can be risked-based and reduce the burden of documentation.

Compliance with protocol

New positive change!

  1. Deviations: All deviations must be documented and reviewed by the PI; however, text has now been added that restricts the requirement to only explain “important” deviations rather than all of them, which I think would reduce expectations placed on investigators for excessive documentation. There is a new expectation for appropriate measures to be implemented to prevent recurrence of deviations, where applicable.

Medical care

  1. Another major change that I anticipate will be welcomed, is that of the ease of the restriction on qualified physicians and dentists to be solely responsible for trial-related medical care and decisions to now also allow other qualified healthcare professionals to be involved in the medical care of trial participants, in line with their normal activities and in accordance with local regulatory requirements.
  2. There has also been a strengthening of text relating to informing the participant’s general practitioner of their trial participation when the participant consents to this. It is no longer just a recommendation.

Safety reporting

All serious adverse events (SAEs) should be reported to the sponsor immediately (after the investigator reasonably becomes aware of the event).

  1. SAE reporting text has been simplified by, for example, removing the text on code numbers. Essentially, SAEs must be reported to the sponsor immediately or as per protocol instructions. This supports the protocol having a proportionate approach to SAE reporting.
  2. The text on reporting SUSARs to the regulatory authority and IRB/IEC has been removed. I assume this was removed as it is a sponsor responsibility.
  3. Also newly added, is the fact that the investigator may delegate activities for safety reporting to qualified investigator site staff but retains the overall responsibility for safety of participants under their responsibility and compliance with the reporting requirements.

Progress reports

  1. Exact timelines for when the investigator should submit written summaries of the trial status to the IRB/IEC has been deleted to now state in accordance with regulatory requirements.

Informed Consent

There have been numerous changes made in the investigator section relating to informed consent of trial participants.

a. The first is the inclusion of additional text to emphasise the importance of the information given and that translations (2.8.6) must be relevant, clear, simple, concise, and understandable to the participant or the participant’s legally acceptable representative and the impartial witness, where applicable, and avoid unnecessary volume and complexity.

  1. Varied approaches including new technology (e.g., text, images, videos, and other interactive methods) may be used in the informed consent process to facilitate the participants’ understanding.
  2. Obtaining consent remotely may be considered where appropriate.
  3. The informed consent process may involve a physical signature or an electronic signature (2.8.8). I wonder if we should consider suggesting to add in our review and recommend the need to allow for a thumbprint or “a mark – X” to be used when dealing with illiterate participants?
  4. Copies to the participant or LAR can be paper-based or electronic.
  5. The PI can now access whether the new information that was made available in the trial (i.e. the protocol amendment) will have an impact on the already enrolled participant’s willingness to continue participation and then determine if re-consent is actually needed for enrolled participants (e.g., depending on where they are in the trial, consideration should be given to whether the new information is relevant only to new participants or also to existing participants). New information should be clearly identified in the revised informed consent materials.I suspect that this should help investigators because it would mean that re-consenting would not be automatically undertaken, as is often seen at present, which I assume would reduce the burden on investigators.
  6. New on minors: A process for re-consent should be considered if, during the trial, the minor reaches the age of legal consent, in accordance with applicable regulatory requirements.
  7. The use of an impartial witness, in case the participant or LAR is unable to read, can be in person or remote.
  8. Does the participant want to be contacted in future about the trial results or the actual treatment they were on (in the case of a blinded trial)? You should only share and make trial results and information on the participant’s actual treatment available to them should they desire it. To document this, I believe it will be good documentation practice if we add this as a tick box to our informed consent process notes and maybe reconfirm this at their last visit. I think this point is a welcome addition in that trial participants can now find out the results of the research they have been involved in, should they wish.

Withdrawal – New section added to end of participation.

  1. We all know that a participant can withdraw at any time, and they do not have to give a reason; however, GCP R3 now elaborates to state the Investigator should put in some effort and respectfully try to understand the reason. I believe the aim is to reduce dropouts from clinical trials as this can severely impact on the trial quality and reliability of the results. New text added covers discussing reasons for withdrawal with the participant and determining if there is a way of addressing the participant’s concern. The guidance now considers different types of withdrawal, and states that there should be follow-up measures to avoid data loss.

Investigational Product

  1. There have been updates made to accommodate decentralized trials, which results in some minor amendments relating to accountability and some additional text stating that the sponsor may facilitate this. There is also a new addition stating that alternative approaches to accountability may be used for authorised medicinal products, which, for example, could allow the use of existing processes for documentation if it is considered sufficient for the trial and reliability of the results, which facilitates the embedding of trials in current clinical practice.
  2. Randomization and unblinding – There has been an update to include a requirement that unblinding processes for use in an emergency by the investigator must be in place at the start of the trial and not subject to any delays or hindrance. I assume this is to ensure that the investigator does not have to wait for authorisation from, for example, the sponsor. A section was added to state that the Investigator should be prepared (Standard operating procedures must be in place) and capable (have the know-how and systems ready) to perform unblinding without undue delay or hinderance.


There are substantial changes relating to records/data/computerized systems. There are broader expectations set out for computerized systems, referencing the new Data Governance section. I think it is important to note that the updates distinguish between computerised systems that are deployed by the investigator/institution and used in normal clinical practice (this could be, for example, the electronic health record) and those deployed and used specifically for clinical trials (this could be, for example, an electronic investigator site file) as there are different expectations in relation to validation responsibilities for each of these.

Does not matter what media you use at your site (paper or electronic, digital images) – the investigator must still ensure the integrity of the data.

i) The site must define prior to study start:

  1. “What is considered source records” and update the definition if needed.
  2. The method of data capturing
  3. The location of your source records

ii) Unnecessary transcription steps in between source records and data capturing should be avoided (example: reported in a printed form, then transcribed to source records, then transcribed to a log, and then entered on the case report form).
iii) The investigator must have timely access to and timeously review data from external sources (example: central lab data, imaging data) which can have an impact on

  1. eligibility
  2. treatment
  3. safety

iv) Investigators must review and endorse reported data at milestones agreed upon with sponsor (for example having an interim analysis).
v) If the site retains trial data (have their own archiving system) they should ensure it is protected from unauthorized access, disclosure, dissemination/alteration, destruction, or loss.
vi) If a principle investigator (PI) leaves a site/closes a site during or after the end of a trial, the sponsor must be notified of who will now retain their documents.
vii) The retaining period is determined by regulatory requirement or the sponsor – whichever period is the longest.
viii) Finally, text has been expanded to include consideration for the co-ordinating investigator to sign the clinical trial report.

Data Handling (significant additions)

It is worth paying particular attention to the significant additions made in this area. These are necessary for updating the guidance to cover the use of new technologies and to address identified gaps in the current guidance. These are:

  1. Ensure integrity and confidentiality.
  2. Focus QA and QC data review on critical data and metadata.
  3. Specifically state in the protocol what data must be collected and how.
  4. Have “fit for purpose” data tools.
  5. Have processes to ensure data integrity in full life cycle.
  6. Safeguard blinding.
  7. Give guidance and instructions to sites and participants on data capturing; navigating systems; data changes; retention; disposal.
  8. To not make changes to data without justification – allow corrections to data to be made by site/participants (but it must just be justified and supported by source).
  9. Ensure site has timely access to data to make decisions (inclusion, safety, IP).
  10. The sponsor must not have exclusive control of data captured in tools.
  11. Seek investigator endorsement at milestones (example: at interim analysis).
  12. Document data management steps prior to analysis.
  13. Restrict access to data tools prior to analysis.
  14. Document and justify deviating from Statistical Analysis Plan (SAP) or changes to data sets after unblinding.
  15. Document what happens to data when participant withdraws consent.

Statistical programming and data analysis

This section is new and must be read in conjunction with ICH E9. This section has to do with the operational aspects of statistical activities of clinical trials.

Clinical trial study reports

This section is new and must be read in conjunction with ICH E 3.

DATA GOVERNANCE – Annex 1, Section 4 (new)

This is an entirely new section that is relevant to the sponsor and the investigator and therefore avoids duplication of expectations in the sponsor and investigator responsibilities sections. With extensive use of computerised systems in clinical trials, that the current addendum partly addressed, this new section provides a higher level of guidance that reflects the more detailed guidance that has been published in this area by Regulatory Authorities such as EMA, FDA and the MHRA’s Data Integrity Guidance.

  1. The beginning of the section again focuses on the quality of the information in the trial being sufficient to provide reliable results and that all processes and systems for the critical data in data life cycle should be implemented proportionately to risks to this and to the safety of participants.
  2. There is a much-expanded section on the maintenance of the blinding of treatment allocation and assessment of inadvertent unblinding, which could affect the reliability of the trial results, stating that it should be part of risk assessment. It states that processes must be in place to protect the blinding. I think this is an important addition because breaches of the blinding, both minor and extensive, have been observed to occur frequently in clinical trials.
  3. The section is based on the data life cycle and includes new and expanded text on data capturing, data verification, metadata, data corrections, data transfers and finalization of datasets prior to analysis. Some significant text that I noted and would like to draw to your attention:

i. Relevant metadata, including audit trails, has significant additions in relation to determining what metadata is available, stating that such data must be decipherable, and which data require review and retention. Audit trail review is particularly welcomed as this is an important aspect of the protection of data integrity.

ii. The data corrections section is expanded and there is new text stating that changes should be supported by source data around the time of original entry. This is useful in relation to changes made to participant diary data that may or may not be appropriate, depending on when the change is made. It has been seen where such data, including endpoint data, has been changed many months after it was originally recorded with nothing available to support making such changes.

iii. Requirement for validation of data transfers. This is an important addition as there have been trials where data has been lost during data transfer due to the lack of adequate transfer processes.

iv. The points relating to finalisation of datasets are valuable additions. It is expected that it must be clear what activities need to be completed. It must be demonstrated that they have been performed to confirm the data has satisfied the expected sufficient quality requirements for the analysis purpose. The use of the word “sufficient” in the text encourages proportionality, I believe, because there is not an expectation for an aim of perfection but a focus on addressing issues that could impact on safety (for example, missing safety data) or reliability of the trial results (lack of follow up data, missing endpoint data, etc.).

Computerised systems

This section explains the importance of the system – whether it is specifically for the purposes of a clinical trial and who has the responsibility for it, as this sets the expectations for the system. Some of the expectations are expanded, e.g., requirement for documented procedures and back up. Some significant additional text that I noted and would like to draw to your attention is:

  1. That those developing systems should understand the GCP requirements. This will help to ensure that the system is compliant. I have seen systems where the functionality was insufficient, e.g., inadequate audit trail, lack of appropriate data change functionality, read-only access not available (for monitoring/audit), etc.
  2. Recommending that participants and healthcare professionals (i.e., end users) are involved in the system design.
  3. Expectations regarding user management and ensuring actions are attributable to an individual.
  4. Setting out of some security expectations.
  5. Expectations on Technical support. This is important as trials often have participants using electronic systems for the purpose of the trial and poor resolution of issues could potentially impact on drop-out rates or increase the amount of missing data.

Validation of computerised systems

Some significant text I noted and draw to your attention:

i. That validation should occur prior to use, that there is a change control process and the need to retain documentation.

ii. Mentioning that protocol-specific configuration data checks and calculations should be validated. This is a welcome addition as there are occurrences where dose changes calculated by eCRFs, described in this new text as critical functionality, have been erroneous or malfunctioned with some cases of mis-dosing of participants as a result.

iii. Ensuring that use of systems with outstanding issues should be justified.

iv. Ensuring that a system is only implemented if it is consistent with the approved protocol. Trials have been seen where updated systems are available for the investigator to use prior to approval by the regulatory authority, or that the site has been told to implement a protocol amendment, but the systems had not been updated. This has caused issues with eligibility in an eCRF (changed in an amendment) and the dose in the IRT system inconsistent with the approved protocol.



Data Acquisition Tool (DAT)
Reference Safety Information (RSI)


Coordinating Committee


Agreement replaced contract
Service Provided replaced CRO
Essential Records replaced Essential Documents
IRB and IEC is now combined
Investigator site replaced Trial Site
Source records replaced Source Documents and Source Data
Trial participant replaced subject

Appendix A: Investigator’s Brochure (minor edits) (Previously ICH E6(R2) section 7)

There are no extensive changes to this section, but there is some minor restructuring at the start. Whilst there is clarification that the sponsor is responsible for ensuring an appropriate Investigator’s Brochure is produced, the key change is inclusion of text concerning the reference safety information as the list of expected adverse drug reactions used for determination of whether a serious adverse reaction is a suspected unexpected serious adverse reaction that requires expedited reporting.

Appendix B: Protocol (Previously ICH E6(R2) section 6)

  1. Text has been added that encourages use of stakeholders in protocol development where appropriate, and the development of a concise and operationally feasible protocol, that reduces unnecessary complexity, but mitigates or eliminates important risks to the rights, safety, and wellbeing of trial participants and reliability of the results. Revisions encourage adaptability in the protocol to reduce deviations and amendments.
  2. Some administrative information requirements have been removed. There has been clarification that the protocol should contain information on processes for participants withdrawing consent and discontinuing treatment and the use of their data.
  3. The changes made include an expectation that the protocol must contain information about the use of data monitoring committees for efficacy and safety assessments and that the protocol should include a description of identified quality factors and associated risks in the trial, monitoring processes and handling of non-compliance.
  4. There is also an expectation that the protocol must contain a reference to the specification of the data to be collected and how it must be collected, including identification of source data in data collection tools rather than just the CRF and that the protocol includes a statement about retention of the trial records.

Appendix C: Essential Records

(Previously ICH E6(R2) section 8)

The guidance has moved from using the term “documents” to the more generic term “records” to broaden the information required to assess the trial conduct to also include data. .

  1. Current requirements on timeliness and organisation of filing, completeness of records, retention, access, and certified copies has been retained.
  2. There has been clarification that the essential records, and therefore the content of the trial mater file (TMF), must be based upon the design and proportional approach applied to the trial.
  3. Tabulation of essential records have been removed. I think that this change is aimed at discouraging the use of the tabulations as a checklist of which records are required, when and where they are located. This is a significant change to the current text section 8 as is now refers to a list of records:

i. that are always expected to be present, called “essential records for all trials” and

ii. those that should they be produced, would also be essential, called “potential essential records”.

d. The “purpose” and “location” columns in current table have been removed and the new tables have amalgamated the “before”, “during” and “after” which led to unnecessary duplication. The opportunity was clearly taken to review the list of records and add some that were frequently produced and retained and used for compliance assessment.

e. There has been, in my view, an encouragement of a thoughtful approach by providing more guidance on what makes a record essential, using some of the information from the current “purpose” column. I think this means it can be used as a guide for clarifying why a particular record might be essential and for training individuals who are involved in generating such records.

f. The revised guidance also addresses the requirement that some essential records are not trial specific and to avoid duplication of such records across ISF or TMFs.

g. The updates have also addressed the use of new technology by referring to “access” of records between parties involved in the trial. Perhaps to state access via internet portals and / or electronic TMF ( eTMFs)  rather than just stating “copies” to clarify the use of service providers and their role in the management of essential records.

h. Finally, the revision has also addressed version control of records.


Cautionary Note: Please be aware that the document referenced is a draft version of the ICH E6(R3) Guideline. As such, the content, recommendations, and guidelines contained within it are not final and may undergo revisions. Changes could be made based on feedback, further expert review, or additional data. Therefore, it’s crucial to monitor updates from the International Council for Harmonisation (ICH) for the release of the final version of this guideline. Always ensure you are referring to the most recent and finalized guidelines in your work.