Impact of the ICH E6(R3) Guideline on Clinical Trial Documents Frequently Prepared by Medical Writers

The third revision of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 guideline, hereafter referred to as ICH E6(R3), became effective on 23 July 2025 in the European Union. ICH E6(R3) emphasizes quality by design and risk-based quality management through identifying the factors (data and processes) critical to ensuring trial quality, assessing potential risks, and implementing proportionate control measures. Other key changes include a focus on patient-centricity, greater transparency, modernized data management practices, and integration of technology.

These shifts introduced by the revised ICH E6 guideline have an important impact on medical writing (please refer to our previous blogpost ‘Impact of the ICH E6(R3) Guideline on Medical Writing’) and obviously also affect the content of the trial-related documents. Especially the increased emphasis on rationale for trial design decisions, risk assessment strategies, and flexibility in operational conduct have an important impact on the trial-related documents. Also the glossary updates (including new and revised terms or definitions as well as removed terminology) affect the trial-related documents.

A detailed breakdown of content changes in clinical trial documents that are frequently prepared by medical writers is provided below.

Investigator’s Brochures

The most important change in the revised guideline with respect to the Investigator’s Brochure or IB is that the list of adverse reactions must include information on their frequency and nature. This reference safety information (or RSI) should be used for determining the expectedness of a suspected serious adverse reaction and subsequently whether reporting needs to be expedited in accordance with applicable regulatory requirements.

Other changes include the following:

The section on effects in humans should provide a summary of ongoing trials where interim results are available that may inform the safety evaluation.

Guidance on overdose and adverse drug reactions now references “previous clinical and nonclinical experience” instead of just human experience. This broadens the evidence base and requires integrating both clinical and preclinical data into this section.

The revised guideline also suggests including the cut-off date for data inclusion on the title page and, where appropriate, a signature page.

Protocols and Protocol Amendments

Several changes were made throughout the sections describing the contents of a Protocol (or protocol-referenced documents) for a clinical trial:

The general information is now limited to sponsor details; the name and other personal information from any expert, investigator, qualified physician, clinical laboratory or other are no longer required.

Information on estimands (when defined) should be added to the trial objectives and purpose.

The trial design should also include the preparation and administration instructions of the investigational product where applicable, unless described elsewhere; the description of schedule of events; and the description of dose adjustment or dose interruption.

The section on selection of participants should include the mechanism for pre-screening, where appropriate, and screening.

In case of withdrawal of consent or discontinuation by the investigator, the process of data handling in accordance with applicable regulatory requirements should be specified in the Protocol.

The section on treatment and interventions should also include criteria for dose adjustments.

Follow-up of participants after events other than adverse events (such as for pregnancies) should also be described. Where any trial-related committees (such as an independent data monitoring committee) are utilized for the purpose of assessing efficacy or safety data, the committees’ procedures, timing and activities should be described in the Protocol or a separate document.

The statistical section has been broadened to include statistical inference methodologies (such as Bayesian design and estimands). The purpose of any planned interim analysis should also be described.

The section on Quality Control and Quality Assurance should describe identified critical-to-quality factors, associated risks and risk mitigation strategies in the trial unless documented elsewhere. Furthermore, it should include a summary of the monitoring approaches that are part of the quality control process for the clinical trial and a description of the process for the handling of noncompliance with the Protocol or Good Clinical Practice (GCP).

Information on Data Handling and Record Keeping should specify the data to be collected and the method of collection. Where necessary, additional details should be contained in a clinical trial-related document. It should also include a statement that records should be retained in accordance with applicable regulatory requirements.

The integration of risk-based approaches with acceptable ranges and the use of an adaptive trial design will minimize the need for Protocol Amendments. In case these need to be created, the rationale for amending the Protocol should be clearly documented.

Informed Consent Forms

Medical writers should be aware that varied approaches (such as text, images, videos and other interactive methods) are allowed in the informed consent process including for providing information to the participant and that electronic and remote consent are permitted. When developing the informed consent materials, the characteristics of the potential trial population and the suitability of the method of obtaining consent should be taken into consideration. When computerized systems are used, trial participants should be given the option to use a paper-based alternative.

ICH E6(R3) adds several new content requirements for the Informed Consent Form or ICF:

Reasonably foreseeable risks or inconveniences to the participant’s partner, where applicable.

Follow-up procedure for participants who stopped taking the investigational product, withdrew from the trial, or were discontinued from the trial.

Data handling procedures, including what happens in the event of the withdrawal or discontinuation of participation (in accordance with applicable regulatory requirements).

A statement that the trial may be registered in publicly accessible and recognized databases (per applicable regulatory requirements).

A statement that trial results and actual treatment, if appropriate, will be made available to participants (if desired).

The revised version modifies wording related to the statement on direct access and confidentiality, clarifies to include a summary of the experimental aspects of the trial, and indicates that contact is needed in case of ‘suspected’ trial-related injury.

If re-consent is needed, new information should be clearly identified in the revised informed consent materials.

For minors, age-appropriate assent is required. Assent information should also consider the maturity and psychological state of the minor population intended to be enrolled, as well as applicable regulatory requirements.

Clinical Study Reports

Since the Clinical Study Report or CSR summarizes how the trial was planned to be conducted and how it was actually done, many topics addressed in the Protocol are also applicable to the Clinical Study Report.

The revised guideline explicitly states that the description of the quality management approach implemented in the trial should include:

A summary of risk assessments, critical-to-quality factors, and mitigation strategies used during the trial.

A summary of important quality issues (including instances in which acceptable ranges are exceeded) and the remedial actions taken.

Post-unblinding data changes and any deviations from the planned statistical analyses (with justification) should be described.

Conclusion

The transition to ICH E6(R3) has an important impact on the content of clinical trial documents. The clinical trial documents must now reflect the shift toward critical thinking and adoption of quality by design and proportionate risk-based approaches to trial design and conduct. Medical writers, as key contributors, need to include all required information in line with the revised guideline to produce compliant clinical trial documents. Their role, together with other involved stakeholders, is to ensure that these clinical trial documents are fit for purpose and safeguard participant safety and data reliability. This means addressing the specific risks of the trial, allowing flexibility, and avoiding unnecessary complexity or burden.

If you would like to learn more about the ICH E6(R3) guideline and its impact on clinical trial documents, please refer to our Emtex Academy training ‘ICH GCP E6(R3) for Medical Writers‘.

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