The International Council for Harmonisation’s (ICH) E6 Good Clinical Practice (GCP) guideline is now updated to revision three (R3) and has reached Step 4, adopted on 6 January 2025.

What does this mean?

Step 4 means the guideline is now considered complete (final) and is endorsed by the ICH Assembly. Adopted means the member regulatory authorities of ICH (such as the FDA, EMA, PMDA, etc.) have formally adopted the guideline into their respective regulatory frameworks. This means the guideline is now part of the official regulatory requirements in these regions and should be followed by stakeholders (e.g., pharmaceutical companies, CROs, researchers) conducting clinical trials or working in drug development.

However, to note – at Step 4 it is not yet fully implemented by individual regulatory authorities in their regions. This will happen at Step 5 of the process.

Step 5 includes two phases:

1. Step 5A (Adoption by Regulatory Members): The finalized Step 4 guideline is adopted by ICH regulatory members into their local laws, regulations, or guidance. This process may include slight region-specific adaptations to align with local requirements.
2. Step 5B (Implementation): After adoption, the guideline is fully implemented and applied in practice by industry stakeholders and enforced by regulators.

How does this impact your clinical research site or organisation?

As stated , the guideline is final and adopted by the member regulatory authorities of ICH so it is a matter of time before sponsors will require all staff working in clinical research to be knowledgeable and trained on the latest updates, ICH GCP R3. So. do not procrastinate and be caught off-guard. Be proactive and get your staff trained at a reputable training organization like TASK Research Academy.

As the changes are not summarised or highlighted nor 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).

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.

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 new section on Data Governance, a responsibility shared by the Investigator and the Sponsor emphasizing the entire data lifecycle, including data capture, secure data, data 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 and a focus to collect only critical data based on a risk analysis and fit for purpose data, according to your trial design.

Essential documents are now referred to as essential records, acknowledging the fact that documents can also be electronic. This whole section again focusses on being “fit for purpose” as it now offers the flexibility to self-access which essential records are relevant to your trial and create your own structured content list based on your trial design.

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.

The layout had a facelift which I believe makes for an easier read! The glossary moved to the back. The 13 principles of R 2 as we know it is now combined into 11 principles 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. The guideline now includes Annex 1, and this is now the placeholder for the sections on Institutional Review Boards/ Independent Ethics Committees , Investigator and Sponsor responsibilities. A whole new section 4, on “Data Governance” was also added to Annex 1. This layout makes provision for additional annexes to be developed and added as the industry develops and stakeholders come up with new innovations in design and conduct.

The layout also introduces Appendices. In the context of ICH guidelines, appendices are supplementary documents or sections that provide additional information, clarification, or examples to support the main guideline. They are not standalone guidelines but are intended to help stakeholders better understand or implement the principles outlined in the core document. Appendices may be advisory rather than mandatory. However, if incorporated into local regulations, their contents may become enforceable. Appendices may be updated separately from the main guideline, allowing ICH to address emerging needs or new technologies without revising the entire guideline.

There are 3 Appendices – A. Investigator Brochure B. Clinical Trial Protocol and Protocol Amendment (s) and C. Essential Records for the conduct of clinical trials.

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.

The 13 principles of ICH GCP E6 (R2) are now combined into 11 principles in 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.

1. There has been a small number of changes to the IRB/IEC section, although some are quite significant.
2. 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.
3. 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.
4. 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.
5. Compensation should be decided prorated/upfront – not based on completion – and the method, amount and 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.
6. Depending on the region, it may be allowed to combine your submission and communication to regulatory authorities and IRB/IEC into one submission (e.g. CTIS, the clinical trial information system used for clinical trial applications in the EU).
7. GCP R3 also recognizes that in some regions the submissions are done by the site (Investigator) and in others by the sponsor.

1. 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 considered. For example, in relation to SUSAR reporting and the removal of the 3-year IRB/IEC record retention requirement.

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

Resources

The PI must be able to prove that they can recruit the numbers by using retrospective or current data.

Responsibilities

Under the section of responsibilities R3 gives a lot of guidance when vendors or other third parties are used. Guidance around their selection, delegation and oversight :

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 3^rd party suggested by the sponsor is appropriate, as the responsibility for oversight of these 3^rd party services remains with the Investigator.
2. The level of oversight over these delegated activities should depend on the nature of the delegated activities and be proportionate to the importance of the data being collected and the risk to participant safety and data reliability.
3. The PI takes ultimate responsibility.to ensure these parties are delegated, qualified, trained on the relevant aspects of the protocol – the training must enable them to fulfil their delegated activities(example when home nurses were arranged by the sponsor).
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.
5. Agreements with vendors must be documented.

Compliance with protocol

New positive change!

Deviations: All deviations must be documented and reviewed by the PI, even those that are communicated via the CRA/sponsor to the site ; however, text has now been added that restricts the requirement to only explain “important” deviations and implement appropriate measures to prevent reoccurrence. Important deviations are defined as those deviations that may significantly impact the completeness, accuracy, and /or reliability of the trial data or that may significantly affect a participants right, safety or wellbeing) rather than all of them, which I think would reduce expectations placed on investigators for excessive documentation.

Medical care

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.

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 unique code identification numbers when reporting to sponsor and text was added to state that the Investigator should also include an assessment on causality. As per R2, SAEs must be reported to the sponsor immediately or as per protocol instructions. R3 now added examples as clarification , for example deaths or events that are endpoints, meaning while SAEs generally require immediate reporting in clinical trials, there might be exceptions outlined in the study protocol. These exceptions often involve SAEs that are considered expected and explicitly stated as objectives of the study. These SAE will still be monitored and tracked however the decision to not require immediate reporting for these specific SAEs is based on the study design and the nature of the research being conducted. This supports the protocol having a risk 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

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 and significant changes made in the investigator section relating to informed consent of trial participants.

1. Obtaining informed consent may be paper based or in electronic format.
2. There is emphasise placed on the importance of the information given to participants to be clear, in a simple language, concise, and understandable to the participant or the participant’s legally acceptable representative (LAR) and the impartial witness, where applicable, and avoid unnecessary volume and complexity.
3. 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 and may involve a physical signature or an electronic signature but should be suitable to the population. When electronic consent is used participants may be given the option to use paper-based approach as an alternative.
4. Obtaining consent remotely may be considered where appropriate.
5. Copies to the participant or LAR can also be paper-based or electronic.
6. A significant update was that 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.
7. New on minors: where a minor is to be included as a participant an age-appropriate assent information should be provided and discussed with the minor as part of the consent process and assent should be obtained. 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.
8. The use of an impartial witness, in case the participant or LAR is unable to read, can be in person or remote.
9. You should only share and make trial results and information on the participant’s actual treatment available to them (in the case of a blinded trial) should they desire it. 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.

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. 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 investigator or delegated investigator site staff should consider explaining to the participant the value of continuing their participation to minimize trial participants withdrawal. In this process, the investigator should ensure that it does not interfere with the participant’s decision to withdraw participation at any time. 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.

Investigational Product

1. The responsibility for IP management still resides with the Investigator, however R3 states that “the sponsor may facilitate aspects of investigational product management” (e.g., by providing forms and technical solutions, such as computerized systems, and arranging shipment /dispensing and administration of IP to trial participants at their location /closer to their location (e.g., at a local pharmacy or a local healthcare centre). Adding this as well as administration of IP by investigator site staff, the participant themselves, a caregiver or a healthcare professional accommodates decentralized trials. However refer to delegation of vendors under “Responsibilities”.
2. Alternative approaches to accountability (documentation around the delivery, the inventory, the use by each participant, the return to the sponsor, and destruction or alternative disposition of unused product(s))may be used for authorised medicinal products, in accordance with local regulatory requirements which, for example facilitates the embedding of trials in current clinical practice.
3. It is stated that the investigator or delegate should explain the correct use of the IP to each participant and should check, at intervals appropriate for the trial, that each participant is following the instructions properly.
4. 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.

Records

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.

a. . The site must define prior to study start:

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

b. 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).
c. 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

• eligibility
• treatment
• safety

d. Investigators must review and endorse reported data at milestones agreed upon with sponsor (for example having an interim analysis).
e. 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.
f. The retaining period is determined by your local regulatory requirements or the sponsor – whichever period is the longest.

The sponsor section has had substantial changes and reorganisation, so this section is unfortunately not going to be a quick or easy read. It’s all about implementing a risk-propitiate approach and shifting the focus to identifying and managing data that will have a significant impact on data credibility and/or participant safety.

Trial Design

1. There must be enough prior data to support the study.
2. Quality built into the design: What factors are critical to the quality of the trial? Manage the risk to those factors.
3. Sponsor must get wider input into the protocol design from variety of stakeholders: participants, health care providers, investigators in protocol and ICF development.
4. The protocol must be operationally feasible (doable)and avoid unnecessary complexity in procedures and tools like data collection– everything must be fit for purpose, the informed consent and even the monitoring plan and data management plan (all operational plans) – everything must be clear, concise, and consistent. The sponsor must not place an unnecessary burden on the participant and the Investigator.

Resources, Allocation of Activities

In this section, the significant change is recognition that activities (i.e., duties and functions of the sponsor) can be delegated, but not their overall responsibility. New text has been inserted, stating that the sponsor must have sufficient resources to conduct the trial.

Qualification and Training (new addition)

This new addition states that the sponsor must use individuals who are appropriately qualified for the tasks assigned to them. (e.g. biostatisticians, clinical pharmacologist, physicians, data managers, auditors and monitors).

Agreements: (new addition)

A new section on agreements brings together aspects of relationships between parties involved in the clinical trial and the delegating of activities.

1. There is now text that states that agreements (with all parties, even committees ) should be documented, rather than just in writing, as in the R2 guideline and the specific duties that were transferred must be documented and those that were not transferred remains with the sponsor.
2. A new requirement added is that agreements should be in place before initiating these delegated activities and that agreements should be updated to reflect any significant change in delegated activities. It should be noted that the signing of the protocol or alternative document to confirm agreement has been removed.
3. The section on Contract Research Organisations (CRO) has been removed. It is important to note that the term “service provider” is now used, of which CRO is an example. I think this is appropriate as it reflects the increased use of small organisations providing specific services/trial activities to sponsors, for example, electronic systems.
4. The responsibility for delegated sponsor activities ultimately remains with the sponsor and has been expanded to include the protection of the rights, well-being, and safety of trial participants and it is required of service providers to report to the sponsor any incident that could impact this and the reliability of the trial results.
5. There is new text where the sponsor must also assess the suitability of a service provider (e.g. their SOPs or performance metrics) and ensure they can adequality undertake the delegated task (s) and supply them with the protocol and other documents that are required for them to undertake the delegated activities and have oversight including on activities that were further sub-contracted .
6. There is new text stating that the sponsor should provide to the investigator the information concerning service providers that the sponsor has identified, where the service provider is undertaking investigator activities (e.g. a protocol procedure that cannot be conducted at the site) to enable the Investigator to select them. I assume this is to ensure that the investigator is appropriately informed about and content with the service provider to which their activities are being delegated.
7. New text states that service providers are required to comply with the aspects of GCP applicable to the activities they are undertaking but acknowledges that these could be met by the service provider’s existing quality system processes – as long as they are fit for purpose in the context of the trial. I assume that this could, for example, be for computer systems validation. If procedures had not been developed specifically for GCP compliance, there could be GCP gaps, for example, if the service provider makes changes to clinical data which is not traceable.
8. A new sentence was added to state that a trial may have one or several sponsors (as per regulatory requirement) – if so, the sponsor must have a clear agreement of responsibilities. If not specified, responsibility lies with both. Here I would recommend a RASCI model to showcase who takes responsibility for what, who is accountable, who only supports and who must just be informed.

Investigator selection

1. New text was added that if in multicentre trials a coordinating Investigator (e.g. Coordinating or National PI) are utilised the selection is the responsibility of the sponsor, and their role and responsibilities must be documented prior to their involvement.

Sponsor Oversight (new addition)

1. New text requires sponsors to ensure that the trial design, conduct and processes will guarantee sufficient quality to ensure reliable trial results and protection of participants’ safety. The trial processes must follow the trial protocol, ethical standards, and applicable regulatory requirements
2. The sponsor should determine the criteria for defining/classifying deviations as “important” (those that significantly impact the completeness, accuracy and reliability of results and those that significantly will impact participants right and safety) and that all decisions are appropriately assessed – the question must be asked: Does the deviation impact on participants’ rights, safety and well-being and the reliability of the trial results? If yes, this is an important deviation.
3. The range and extend of oversight measures must be fit for purpose. The sponsor must tailor their oversight according to the complexity of the trial and related to the risks associated with trial. These factors must guide the sponsor in their selection of investigators, service providers, quality assurance and quality control processes, to ensure their oversight is proportionate to the complexity and risk of the trial (fit for purpose).
4. It also requires the sponsor to ensure appropriate escalation and follow-up of issues identified in a timely manner. I think this is useful additional text that reminds sponsors that, whilst activities can be delegated, responsibility cannot, therefore they need to oversee the conduct of the trial.
5. The sponsor is encouraged to perform interim analysis to access the progress of clinical data, safety data, and endpoints. They may appoint an Independent Data Monitoring Committee (IDMC) to assist to recommend if the trial should continue.
6. The sponsor may also appoint an endpoint assessment committee to review reported endpoints, however they should be blinded when performing endpoints assessments regardless of whether the trial itself is blinded.
7. Committees must include members with relevant expertise, have no conflict of interest, have written SOPs and document their decisions.

Quality Management

In the quality management section, the current addendum text has been essentially retained, but has had some restructuring, so that it appears as an introductory line to the whole sponsor section again encouraging risk-proportionate approaches.

It is now relatively common to see sponsors conducting risk assessment of a trial, so it is welcome that the guideline expands and continues to encourage risk-based approaches. The assessment is a key feature of adopting a proportionate approach to management of the trial, the processes applied, and how compliance with GCP will be achieved. Often seen, however, is a lack of a comprehensively documented risk review (identifying those factors that are likely to have a meaningful impact on participant’s rights, safety and wellbeing and the reliability of results ) where R3 is now requesting the documentation of a sponsor’s risk review and to reassess when there is change (e.g., a protocol amendment), and make the necessary changes to the trial’s quality management processes. The sponsor should describe the quality management approach implemented in the trial in the clinical trial report (see ICH E3_Strucure and Content of CSR).

Quality Assurance and Quality Control

a) Auditing

Most of the text in the audit section is unchanged, but some new significant text has been added to state that the sponsor audits should be proportionate to the risks associated with the trial and that the audit is separate from routine monitoring and should assess whether the processes in place to manage and conduct the trial are effective and compliant.

b) Monitoring

The monitoring section has undergone extensive revision and reorganisation. They have taken the opportunity to fully integrate the Addendum as part of a restructure of the entire section and to modernise it further. In summary: The current sections on Purpose and the Extent and Nature of Monitoring have been replaced with an introduction, a new section added on Investigator Site Monitoring, including that this could be remote, a new section added on Centralised Monitoring, and the Monitoring Plan section brought forward from its current position. The current section on monitor selection and qualifications has been deleted.

The revised text does not contain the text stating that central monitoring could be used in exceptional circumstances. Instead, it is describes as an important component of monitoring activities that are part of a risk-based approach and it compliments and may reduce the extend and/ frequency of on-site monitoring by flagging the need for a targeted site visit. It can also be used on its own.

There is no longer a statement in the guideline that, “in general there is a need for site monitoring”, which is a significant change. The introduction emphasises that monitoring activities cannot be performed by those involved in the clinical conduct of the trial and that every site should have an assigned monitor as their contact point.

The description of site monitoring includes a list of activities performed by a monitor and frequency of monitoring depending on factors like the complexity of the trial, if its blinded, the number of participants, the safety profile of the IP and endpoints.

R3 recognises remote activities, including remote access to the source records and other electronic systems. I think that these have been introduced because of the experience with monitoring trials during the pandemic.

In the section on Investigator site monitoring text was added to state that monitoring at the site includes monitoring of their pharmacies and local laboratories as appropriate.

The monitoring plan has been updated to add that monitoring should be tailored to the identified risks to the reliability of the results, site capabilities and potential burdens, and that it should also address important data (e.g. primary endpoint data) and processes around participant safety, performed outside of the investigator site.

The current section on Monitor’s Responsibilities has been removed and instead it is now called Monitoring Activities, as these are not restricted to role of the monitor. For example, staff involved in central monitoring activities would also be involved. I think this is a sensible change to reflect modern monitoring practices. New sections of activities are added. These are:

• Communication with Parties Conducting the Trial,
• Investigator Site Selection, Initiation, Management & Close Out,
• Monitoring of Investigational Product Management, and
• Monitoring of Clinical Trial Data.

Review of the Monitoring Activities section reveals additions made, including a requirement to focus efforts on important deviations and that actions taken in relation to deviations, errors and omissions should be proportionate to their importance. New requirements for monitoring are to clarify the protocol source records and location of these, verifying that blinding is maintained. Review and reporting of participant recruitment and retention rates have also been added. Some additional text has been added concerning the monitoring of investigational products. These include confirming that products are used within shelf life, used in accordance with randomisation, that instructions on the investigational products are also communicated to the investigator, their staff and participants. New text states that some of these considerations may not be applicable to products that are available on the market. This, I assume, is related to the fact that clinical trials may use authorised products in existing systems for routine clinical practice, therefore expectations and subsequent monitoring requirements would need to be adapted.

Current sections on Monitoring Procedures and Monitoring Reports have been retained but have been modified. Monitoring procedures have been updated to be more general, no longer referring just to monitors but persons (to maybe also include central monitors). It specifically mentions them following the monitoring plan and replaces SOPs, which is a useful addition because I have seen trials where a suitable risk-based monitoring plan is developed, but then not fully implemented. The section on Monitoring Report has changed significantly to become more generalised so that it covers both on-site and centralised monitoring.

In the Monitoring of Clinical Trial Data section there is new text relating to selection of data for verification based on a sample of data supported by data analytics. There is also new text stating that the verification of data should be of those identified as critical in the monitoring plan. I think that this is a clear encouragement of proportional data checking.

There is current text that has not been included, such as:

• Checks for unauthorised delegation of activities.
• Documenting verification of dose modifications.
• Documenting concomitant medications and intercurrent illnesses in the Case Report Form (CRF).
• Reporting missed visits, missed tests, withdrawals, and dropouts in the CRF.

Although I believed these are implied in the activity of reporting of non-compliances – if their impact is significant/important it will be reported.

Non-Compliance

There have been some minor modifications in the Non-Compliance section: that actions by the sponsor should be appropriate and proportionate to secure compliance, that issues that could significantly impact participants’ rights, safety and well-being or the reliability of trial results require reporting to the Regulatory Authority(ies) and IRB/IEC, as appropriate. There is also additional text stating that non-compliance that persists despite efforts at remediation would cause the sponsor to terminate the investigator/institution’s or service provider’s participation in the trial.

Safety Assessment and Reporting.

Current sections on Safety Information and Adverse Drug Reaction Reporting have seen significant additions that are required to be noted and are contained in this new section.

1. New text has been added to state that the Investigator’s Brochure or basic product information forms the basis of the safety assessment, i.e., for assessing expectedness, and that this must contain the Reference Safety Information.
2. The sponsor should review safety data in a timely manner with text now including the review of reported unfavourable medical events in participants before IP was administered (e.g. screening) as this mat result in the update of the protocol, IB or ICF.
3. The sponsor should expedite the reporting of all SUSAR cases, in line with ICH 2A Clinical Safety Data Management, to the Regulatory Authority(ies) and IRB/IECs.
4. It is stated that reporting of such cases to IRB/IEC and investigators may be subject to different expectations; for example, in some regions, periodic reporting of line listings with an overall safety assessment may be appropriate.
5. Additional text states that alternative arrangements for safety reporting could be implemented and agreed on prospectively by Regulatory Authorities when described in the trial protocol. It refers to ICH E19. I suggest that this clearly encourages a risk-based approach to safety reporting when it is considered appropriate by the sponsor and the Regulatory Authority(ies).
6. New text addresses the need for reporting of urgent safety issues without delay in accordance with regulatory requirements and there are new expectations concerning the actions taken to manage immediate hazards to trial participants, in terms of remedial actions and necessary protocol amendments.

Insurance/Indemnification/Compensation to Participants and Investigators

There appears to be no significant changes.

Investigational Product

1. Text has been changed to state that the sponsor should ensure that an Investigator’s Brochure is developed and updated as significant new information becomes available. This slight change would cover situations where the sponsor may not be the manufacturer of the investigational drug and therefore not producing the Investigator’s Brochure themselves.
2. In the section titled Supplying and Handling Investigational Products, current text has been retained with the addition of the option for sponsor to supply IP directly to trial participants. It also states that instructions should be available for trial participants (which would potentially occur in decentralised trials). Further changes made include new text on timely delivery for supply to site or trial participants to ensure no interruptions and continuation of treatment.
3. There is new text relating to retention of IP samples to double-check its properties if needed to help ensure the accuracy and reliability of the trial results. Detailed records of the medication’s characteristics must be kept unless if the medication used in the trial is already approved for use and is not altered in any way, the manufacturer may be responsible for keeping the samples instead of the sponsor. These changes have clearly been made in relation to trials involving authorised medicinal products, for which I assume it would mean that unmodified authorised medicinal products could be released for normal clinical practice after the trial as part of alternative disposition and acknowledging there is no need for retention of samples of such an investigational product.

Data and Records (significant additions)

a. Data Handling

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

• Ensure integrity and confidentiality.
• Focus QA and QC data review on critical relevant data and metadata.
• Pre-specify in the protocol what data must be collected and how.
• Have “fit for purpose” data tools ready before the trial starts.
• Have processes to ensure data integrity in full data life cycle.
• Safeguard blinding – maintain the blind during data entry and processing.
• The sponsor must give guidance and instructions to sites and participants on data capturing; navigating systems; data changes; retention; disposal.
• The sponsor may not make changes to data without documented justification and in agreement with the Investigator – allow corrections to data to be made by site/participants (but it must just be justified and supported by source).
• Ensure site has timely access to data collected even from external sources to enable the site to make decisions (e.g. on elligibilty, safety, IP).
• The sponsor must not have exclusive control of data captured in tools.
• Seek investigator endorsement at milestones (example: at interim analysis) and ensure the ability to access and change the data is managed.
• Restrict access to data tools prior to analysis.
• Document and justify deviating from Statistical Analysis Plan (SAP) or changes to data sets after unblinding.
• Document what happens to data when participant withdraws consent.
• Computerised systems were added to R3 – refer to the new section on Data Governance below which is a shared responsibility between sponsor and the Investigator. In summary the sponsor is responsible for ensuring the proper selection, implementation, and oversight of all computerized systems used in a clinical trial, with a focus on data integrity, system security, and user accountability.

b. Statistical programming and data analysis (New)

This section is new and must be read in conjunction with ICH E9. A comprehensive statistical analysis plan (SAP) should be developed, outlining the approach to data analysis. Rigorous quality control procedures for all statistical programming and data analysis activities must be implemented and documented. Data traceability for all transformations and derivations is crucial. Inclusion/exclusion criteria for participants in analysis sets should be pre-defined, and the rationale for any exclusions must be clearly documented. Deviations from the SAP or post-unblinding data changes should be limited to exceptional circumstances, documented, justified, and appropriately authorized. All statistical programming records, including quality control/validation activities, should be retained. Outputs must be traceable, dated, time-stamped, and protected from unauthorized changes.

Clinical trial study reports (New)

• Premature Termination/Suspension: If a trial is prematurely terminated or suspended, the sponsor must promptly inform investigators, regulatory authorities, and the IRB/IEC about the decision and its reasons.
• Clinical Trial Reports:
  • The sponsor must ensure that clinical trial reports (including interim reports) are prepared and submitted to regulatory authorities as required.
  • Reports in marketing applications must comply with ICH E3 or applicable regulatory standards.
  • Consider including the coordinating investigator as a signatory on the clinical trial report.
  • After trial unblinding and data analysis, the sponsor should generally:
    • Make trial results publicly available.
    • Provide investigators with information about their participants’ treatment (for blinded trials) and the trial results.
    • Provide participants with a non-technical and non-promotional summary of trial results.

In essence, this section emphasizes the importance of timely and transparent reporting on all aspects of the clinical trial, including its progress, outcomes, and any premature terminations.

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:
   • 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.
   • 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.
   • 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.
   • 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:

1. That validation should occur prior to use, that there is a change control process and the need to retain documentation.
2. 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.
3. Ensuring that use of systems with outstanding issues should be justified.
4. 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.

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.

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. R3 now allows the site to assess whether a record is essential and must be retained by considering the 28 criteria listed in R3. Such assessment, whilst important, is not required to be documented. The site can now create their own unique “structured content list for storage repository(ies)” to prospectively identify essential records.
2. Applying the above criteria, the trial records that are considered essential are listed in the Essential Records Table, and these should be retained when produced (The rule of thumb – If a record is generated for your trial, it is an essential record).
3. The R3 essential records table deleted the “purpose” and “location” columns in the R2 table, and the new table amalgamated the “before”, “during” and “after” which led to unnecessary duplication, into one list of essential records using an asterisk (*) to indicate which essential records are expected to be generated and filed before trial starts.
4. For some trial records listed in the Essential Record Table, their presence and nature are dependent on the trial design, trial conduct and risk proportionate management of the trial and may not be necessary to produce. This is maybe to prevent having file notes explaining some essential records’ non-relevance to your trial.
5. R 3 also acknowledges that the trial master file (TMF) at site can be referred to as the Investigator Site File (ISF).
6. 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.
7. Another welcoming update was the acknowledgement that some essential records are hosted with the sponsor during the trial (e.g. when an Investigator access a sponsor portal to acknowledge SUSAR reports). These records may remain on this portal during the trial, on condition that they are acknowledged by the Investigator and have an audit trail and is accessible during audits but must be filed in the ISF at the end of the trial.
8. The same applies to vendors. When an activity e.g. ECG was delegated to a service provider and they have the reports on their system, there must be arrangements made to access and manage it throughout the and for their retention following completion of the trial.
9. Finally, the revision has also addressed version control of records. Records must be identifiable, and version controlled and if appliable must have an author, reviewers, approvers and must be signed and dated