Impact of E6R3 on medical writing
Regulatory clinical writing involves protocol, informed consent documents, investigator brochures, patient diaries, clinical study reports and many more. Apart from therapeutic area and indication specific nuances, product specific guidelines, country specific regulatory guidelines, ICH GCP guidelines are cornerstone for development of clinical trial design and operations.
ICH E6 guideline provides general framework for Good Clinical Practice to be followed during conduct on an interventional clinical trial. ICH has adopted third revision of the guideline on 06 January 2025 and it is in process to be adopted by major ICH countries. E6R3 has tried to stress on fostering a quality culture and proactively designing quality into clinical trials and drug development planning, identifying factors critical to trial quality, and engaging interested parties, as appropriate, using a proportionate risk-based approach. Below are the key impacts on various documents in new adopted guidelines from medical writing perspective:
Impact on Protocol:
Principles of GCP:
Principle 1: Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with GCP and applicable regulatory requirement(s). Clinical trials should be designed and conducted in ways that ensure the rights, safety and well-being of participants.
- The rights, safety and well-being of the participants are the most important considerations and should prevail over interests of science and society.
- Foreseeable risks and inconveniences should be weighed against the anticipated benefits for the individual participants and society. A trial should be initiated and continued only if the anticipated benefits justify the known and anticipated risks.
- When designing a clinical trial, the scientific goal and purpose should be carefully considered so as not to unnecessarily exclude particular participant populations. The participant selection process should be representative of the population groups that the investigational product is intended to benefit, once authorised, to allow for generalising the results across the broader population. Certain trials (e.g., early phase, proof of concept trials, bioequivalence studies) may not require such a heterogeneous population.
Impact: Inclusion and exclusion criteria should be thoughtfully designed and meticulously drafted to align with the trial objectives. Often, Phase II and Phase III protocols show minimal differences apart from variations in sample size, with generalized criteria applied across protocols — some of which may not be truly essential. A critical gap observed in many protocols is the absence of Go/No-Go decision criteria, which are vital for risk-based decision-making. Every protocol should define these criteria upfront to enable data-driven decisions at key milestones, enhancing trial efficiency and patient safety.
Principle 4. Clinical trials should be scientifically sound for their intended purpose and based on adequate and current scientific knowledge and approaches.
4.2 Clinical trials should be scientifically sound and reflect the state of knowledge and experience with the investigational product(s), including, if applicable, the condition to be treated, diagnosed or prevented; the current understanding of the underlying biological mechanism (of both the condition and the investigational product); and the population for which the investigational product is intended.
4.3 There should be periodic review of current scientific knowledge and approaches to determine whether modifications to the trial are needed, since new or unanticipated information may arise once the trial has begun.
Principle 5. Clinical trials should be designed and conducted by qualified individuals.
5.1 Individuals with different expertise and training may be needed across all phases of a clinical trial, such as physicians, nurses, pharmacists, scientists, ethicists, technology experts, trial coordinators, monitors, auditors and biostatisticians. Individuals involved in a trial should be qualified by education, training and experience to perform their respective task(s).
Impact: The involvement of Key Opinion Leaders (KOLs) in protocol reviews will become more prominent to ensure high-quality scientific input. Medical writing teams from Sponsors and CROs must engage subject matter experts for comprehensive, in-depth protocol assessments. The rising demand for adaptive clinical trial designs, dynamic statistical considerations, and a flexible approach to protocol amendments will drive the need for well-defined, robust SOPs to govern protocol writing, review, and modifications.
Principle 6. Quality should be built into the scientific and operational design and conduct of clinical trials.
6.2 Factors critical to the quality of the trial should be identified prospectively. These factors are attributes of a trial that are fundamental to the protection of participants, the reliability and interpretability of the trial results and the decisions made based on those trial results. Quality by design involves focusing on critical to quality factors of the trial in order to maximise the likelihood of the trial meeting its objectives.
Impact: Protocols should incorporate robust withdrawal and study termination criteria tailored to each trial, following a risk-based approach. These criteria should be designed considering the trial indication, emerging safety data, and the willingness of both the participant and investigator to continue study participation. Clearly defined, study-specific withdrawal guidelines will ensure participant safety, ethical conduct, and scientific integrity throughout the trial. Endpoints based on Quality of Life and Human Factors (treatment acceptance) will also play major role in decision making.
Principle 8. Clinical trials should be described in a clear, concise, scientifically sound and operationally feasible protocol.
8.1 A well-designed trial protocol is fundamental to the protection of participants and for the generation of reliable results.
8.2 The scientific objectives of any trial should be clear and explicitly stated in the protocol.
8.3 The clinical trial protocol as well as the plans or documents for the protocol execution (e.g., statistical analysis plan, data management plan, monitoring plan) should be clear, concise and operationally feasible.
Annexure 1 Section 3.1 Trial Design
3.1.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy data (e.g., from nonclinical studies and/or clinical trials and/or real-world sources) are available to support human exposure by the route, at the dosages, for the duration and in the trial population to be studied.
3.1.2 Sponsors should incorporate quality into the design of the clinical trial by identifying factors that are critical to the quality of the trial and by managing risks to those factors.
3.1.3 Sponsors should consider inputs from a wide variety of interested parties, for example, healthcare professionals and patients, to support the development plan and clinical trial protocols as described in ICH E8(R1) and when developing the informed consent materials and any other participant-facing information.
3.1.4 The sponsor should ensure that all aspects of the trial are operationally feasible and should avoid unnecessary complexity, procedures and data collection. Protocols, data acquisition tools and other operational documents should be fit for purpose, clear, concise and consistent. The sponsor should not place unnecessary burden on participants and investigators.
Impact: Study endpoints should be carefully selected, scientifically justified, and supported by robust scientific data. The protocol must provide detailed design considerations along with appropriate literature references to strengthen its scientific rationale. All associated plans, such as the Statistical Analysis Plan, Data Management Plan, and Safety Management Plan, should be clearly referenced in relevant sections.
Clinical operations teams should actively participate in protocol reviews to ensure that study requirements are operationally feasible and practically implementable. Establishing well-structured protocol review committees is essential, involving key stakeholders such as clinical operations, subject matter experts, statisticians, data management professionals, pharmacovigilance teams, legal representatives (as applicable), and other ad hoc experts to ensure a holistic, high-quality protocol development process.
Annexure 1 Section 3.9 Sponsor Oversight
3.9.7 The sponsor may consider establishing an IDMC to assess the progress of a clinical trial, including the safety data and the efficacy endpoints, at intervals and to recommend to the sponsor whether to continue, modify or stop a trial.
3.9.8 Where appropriate, sponsors may also establish an endpoint assessment/adjudication committee in certain trials to review endpoints reported by investigators to determine whether the endpoints meet protocol-specified criteria. To minimise bias, such committees should typically be blinded to the assigned treatments when performing their assessments, regardless of whether the trial itself is conducted in a blinded manner.
Impact: The protocol should clearly outline the role of Independent Data Monitoring Committee (IDMC) or Data Safety Monitoring Board (DSMB) in the study, along with a brief description of their responsibilities and decision-making process. It should define how these committees will operate, including data flow mechanisms, blinding procedures, and the type of subject matter experts (such as clinicians, statisticians, and pharmacovigilance experts) who should be part of the committee.
Additionally, the protocol must specify how the committee’s recommendations will be documented, communicated to the sponsor, and how resulting decisions will be implemented, including the process for protocol amendments based on interim findings or safety concerns. This ensures transparency, independence, and timely decision-making to safeguard participant safety and trial integrity.
Appendix B Clinical Trial Protocol and Protocol Amendments
The content has been updated to:
• Highlight the importance of the protocol, such as:
o Building adaptability into the protocol, for example, by including acceptable ranges for specific protocol provisions, can reduce the number of deviations or in some instances the requirement for a protocol amendment.
• Encourage simplicity and clarity.
o Clinical trials should be described in a clear, concise and operationally feasible protocol. The protocol should be designed in such a way as to minimise unnecessary complexity and to mitigate or eliminate important risks to the rights, safety, and well-being of trial participants and reliability of data.
• Address the implication for withdrawal of consent or discontinuation by the investigator.
• Broaden the statistical section to include statistical inference methodologies (e.g., Bayesian design and estimands).
Impact: Statisticians will play a crucial role in protocol development, with a growing demand for highly experienced professionals to support complex trial designs. They must stay updated with emerging statistical methodologies, participate in scientific forums, and contribute to focused group discussions to bring the latest insights into protocol design.
Pharmacologists involved in protocol development should also have a strong understanding of statistical considerations to ensure alignment between clinical and statistical aspects. Special attention must be given to the implications of participant withdrawals and dropouts, as these factors can significantly impact the statistical power, sample size estimation, and overall trial cost.
A collaborative approach involving clinical operations experts, medical reviewers, and statisticians is essential to accurately assess these risks and derive realistic, data-driven estimates, ensuring both scientific robustness and operational feasibility.
Impact on Informed Consent Documents:
Principles of GCP:
2. Informed consent is an integral feature of the ethical conduct of a trial. Clinical trial participation should be voluntary and based on a consent process that ensures participants (or their legally acceptable representatives, where applicable) are well-informed.
2.1 Freely given informed consent should be obtained and documented from every participant prior to clinical trial participation. For potential participants unable to provide informed consent, their legally acceptable representatives, acting in the participants’ best interest, should provide consent prior to clinical trial participation. These potential participants should be informed about the trial in a manner that facilitates their understanding. In the event that a minor is a participant, assent should be collected from that minor, as appropriate, and in accordance with local regulatory requirements (see ICH E11(R1) Clinical Investigation of Medicinal Products in the Pediatric Population).
2.2 The process and information provided should be designed to achieve the primary objective of enabling potential trial participants to evaluate the benefits, risks and burden of participating in the trial and to make an informed decision on whether or not to participate in the trial. The information provided during the informed consent process should be clear and concise so as to be understandable by potential participants or legally acceptable representatives.
2.3 The informed consent process should take into consideration relevant aspects of the trial, such as the characteristics of the participants, the trial design, the anticipated benefits and risks of medical intervention(s), the setting and context in which the trial will be conducted (e.g., trials in emergency situations), and the potential use of technology to inform participants (or their legally acceptable representatives) and obtain informed consent.
2.4 In emergency situations, where consent cannot be obtained prior to trial participation, consent should be obtained from the participant or their legally acceptable representative as soon as possible in accordance with applicable regulatory requirements and the processes approved by the institutional review board/independent ethics committee (IRB/IEC).
Impact: Informed Consent Documents (ICDs) should be thoughtfully designed to convey all essential information to participants in simple, lay-friendly language, enabling them to make informed decisions about their participation in the study. Innovative approaches like infographics, audio-visual aids, and other interactive methods can be adopted to enhance participant understanding, especially for complex studies.
Assent forms for pediatric participants should also be carefully crafted to ensure age-appropriate language. The Informed Consent Form must clearly identify key stakeholders involved in the consent process, including the investigator, delegated consent executor, participant, Legally Authorized Representative (LAR), and impartial witness (if applicable).
ICDs should be designed to support both paper-based and electronic consent systems, with built-in adaptability for evolving technologies. With the rise of decentralized clinical trials (DCTs), ensuring compliance with electronic consent guidelines will be essential. Translations into local languages must undergo rigorous quality review to ensure the accuracy and essence of information are preserved without compromising clarity or context.