The facelift of R2 of ICH GCP

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 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.

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.

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.

Resources

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

Responsibilities

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.
2. The PI takes ultimate responsibility.to 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.

2. 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.
3. Obtaining consent remotely may be considered where appropriate.
4. 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?
5. Copies to the participant or LAR can be paper-based or electronic.
6. 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: 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. 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.

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.

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.

The sponsor section has had substantial changes and reorganisation, so this section is unfortunately not going to be a quick or easy read.

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 them and implement risk proportionate processes.
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)to avoid unnecessary complexity, complex tools – everything must be fit for purpose, even the monitoring plan and data management plan: everything must be clear, concise, and consistent.

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.

Agreements: (new addition)

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

1. There is now text that states that agreements should be documented, rather than just in writing, as in the current guideline.
2. A new requirement added is that agreements should be in place before initiating the activities and that agreements should be updated to reflect any significant change in delegated activities.
3. Current text moved here is that responsibilities of co-ordinating investigators and other investigators need to be documented prior to starting the trial.
4. It should be noted that the signing of the protocol or alternative document to confirm agreement has been removed.
5. 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.
6. The sponsor’s responsibility for delegated activities has been expanded to include 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.
7. There is new text relating to the requirement for sponsors to assess service providers, including obtaining relevant information for this and for their ongoing oversight.
8. The sponsor must also provide the service provider with the protocol and other documents that are required for them to undertake the delegated activities.
9. 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. 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.
10. 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. 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 or retains essential records. This text replaces the current text stating that reference to sponsor includes CROs and their trial-related duties.
11. 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 an agreement of responsibilities. If not specified, responsibility lies with both.

Sponsor Oversight (new addition)

1. Whilst this section retains text relating to independent data monitoring committees moved from the old Trial Management, Data Handling and Record Keeping section, with additional text concerning expertise and conflict of interests, there is also new text concerning committees that are involved with the adjudication of endpoints. New text requires sponsors to ensure a trial design, conduct and processes that will guarantee 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 ensure criteria are in place for defining deviations as “important” 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. There is a requirement that the 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.

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 encouraging risk-proportionate approaches.

It is now relatively common to see sponsors conducting and documenting 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 – for example, failing to reassess when there is change (e.g., a protocol amendment), and make the necessary changes to the trial’s quality management processes.

Auditing

Most of the text in the audit section is unchanged, but some new significant text has been added to state that the audits should be proportionate to the risks associated with the trial and that the audit should also assess that processes in place to manage and conduct the trial are effective and compliant. The auditor no longer needs to be independent of the systems, just of the clinical trial, and the requirement for the auditor’s qualifications to be documented has been removed.

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.

1. The revised text does not contain the text stating that central monitoring could be used in exceptional circumstances and instead describes it as an important component of monitoring activities that are part of a risk-based approach.
2. The text on the purpose of monitoring has been replaced with aims in the introduction and the section on the accuracy of data has been replaced with a section on the reliability of trial results, with the text on compliance now covered in the introduction to the section. 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. The description of site monitoring includes amendment of activities and frequency dependent on knowledge gains, allows 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.
3. The monitoring plan has been updated to add that monitoring should be tailored to the identified risks to the reliability of the results, that it should ensure oversight whilst considering site capabilities and potential burden, and that it should also address key data and processes performed outside of the investigator site.
4. 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:
   1. Communication with Parties Conducting the Trial,
   2. Investigator Site Selection
   3. Initiation, Management & Close Out,
   4. Monitoring of Investigational Product Management, and
   5. 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 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 and their staff and other relevant individuals and parties. 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.

e. 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. It specifically mentions the monitoring plan and replaces SOPs with applicable monitoring procedures. Inclusion of a section called Following the Monitoring Plan 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.

f. In the Monitoring of Clinical Trial Data section there is new text relating to selection of data for verification based on samples 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.

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

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

However, I assume that these would be covered under the more general aspects of monitoring clinical trial data.

Communication to IRB / IEC – (minor edits)

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 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. New text emphasises that the sponsor should periodically review the emerging safety information and update the Investigator’s Brochure and any other documents as necessary.
3. The focus of expedited reporting of SUSAR cases is now for the awareness of the Regulatory Authority(ies). It is stated that reporting of such cases to IRB/IEC and investigators may be subject to different expectations; for example, based on urgency and the use of aggregate information rather than individual case reports.
4. 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).
5. 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. 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 supply directly to trial participants. It also states that instructions should be available for trial participants (which would potentially occur in decentralised trials).
3. Further changes made include new text in the section titled timely delivery for supply to trial participants to ensure no interruptions and continuation of treatment.
4. There is new text relating to alternative disposition of investigational products and for authorised medicinal products. New text has been added stating that samples of these do not need to be retained. 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.

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.