Introduction: Obtaining informed consent is a cornerstone of ethical clinical research. It’s the process by which potential participants learn about a trial, understand its risks and benefits, and voluntarily decide whether to join. ICH E6(R3) updates Good Clinical Practice standards to ensure the consent process stays effective and relevant in modern trial settings. Key themes include making consent information clear and concise, accommodating new formats like electronic consent, and reinforcing ethical considerations like assent from minors and consent in emergencies. In this blog, we explore how informed consent expectations have evolved in the E6(R3) era and what investigators and sponsors should do to align with these changes.
Concise and Comprehensible Consent Information
One of the explicit changes in ICH E6(R3) is the requirement that informed consent information be “clear and concise.” Past trials often suffered from extremely long, legalistic consent forms – some stretched 20-30 pages, overwhelming prospective participants. Regulators recognized that overly complex forms defeat the purpose of informed consent. Under E6(R3), the emphasis is on quality of understanding over quantity of text.
Practical implications:
- Focus on Key Information: Consent forms and discussions should prioritize the essential information a reasonable person would need to make a decision. This includes the study’s purpose, duration, required procedures, key risks, potential benefits, and alternative treatments if applicable. It’s advisable to highlight these elements up front, perhaps in a one-page synopsis or through visual aids like diagrams or bullet points, before delving into finer details. The U.S. FDA and EU regulators have similarly encouraged a “key information” summary at the beginning of consent forms. Adopting that approach will satisfy E6(R3)’s call for clarity.
- Simplify Language: Use plain language and avoid unnecessary jargon or technical terms. Where medical terminology is needed, explain it in lay terms. For example, instead of “We will perform phlebotomy at each visit,” say “We will draw a small sample of blood (about one teaspoon) at each visit.” Test the form’s readability – a good target is around an 8th-grade reading level or lower. Under E6(R3), an ethics committee (IRB/IEC) reviewing the consent will be looking for understandability. Many IRBs have started sending lengthy forms back for revision, and E6(R3) is squarely on their side in this regard.
- Conciseness vs. Completeness: Striking the right balance is important. “Concise” doesn’t mean omitting important information. All required elements (as per applicable regulations and GCP) must still be provided. But it encourages cutting out excess – redundant wording, overly detailed scientific explanations that aren’t crucial for decision-making, and extraneous text not relevant to the participant’s choice. One strategy is to use appendices or separate information sheets for ancillary information (for instance, a detailed privacy notice or separate genetic testing information) rather than cluttering the main consent document. The participant can receive those too, but the primary narrative remains focused.
Embracing Flexible Consent Modalities: eConsent and Remote Consent
Perhaps the most modern aspect of E6(R3) is its acceptance of electronic and remote consent processes. The updated guideline confirms that electronic methods can be used to obtain informed consent and that consent may be obtained in various settings, including remotely, as long as it meets all ethical and regulatory requirements. This reflects the industry’s learning during COVID-19 and the rise of decentralized trials.
Key points for implementation:
- Electronic Informed Consent (eConsent): This refers to using digital platforms (tablets, computers, smartphones) to deliver consent information and capture consent signatures. E6(R3) acknowledges eConsent is permissible. The advantages are many: interactive multimedia content (videos, quizzes, graphics) can improve comprehension; electronic records can integrate easily into trial databases; and tracking is improved (time-stamped proof of when consent was given, etc.). If using eConsent, ensure the system is secure (compliant with data protection laws) and provides an option for the participant to download or print the consent document for their records. Also, validate that the system captures the signature (or equivalent electronic acknowledgement) in a manner that is legally recognized – many jurisdictions accept electronic signatures, but often require specific technology (e.g., audit trails, authentication) to be in place.
- Remote Consent via Phone/Video: E6(R3) also allows that consent can be obtained without the person being physically present with the investigator, in certain circumstances. For example, during a pandemic lockdown, an investigator might email or post a consent form, then discuss it over a video call with the patient and obtain verbal consent on camera followed by a return of a signed document by electronic means. To do this properly, sites should have IRB/IEC approval for the remote process and a plan to verify participant identity (to ensure the person signing is indeed the subject or their legal representative). Documenting identity verification is explicitly mentioned in E6(R3) – for instance, confirming personal information or using a secure login can suffice.
- Assent in Minors and Consent in Special Situations: E6(R3) underscores that for participants who are minors, their assent (agreement) should be sought in addition to the parent/guardian’s consent, appropriate to the child’s age and maturity. Likewise, it references emergency settings – where consent might need to be deferred or obtained under urgency. While such scenarios are governed by local regulations, GCP essentially says to follow those laws but still ensure the participant (or next of kin) is informed as soon as possible. The updated guideline simply reminds stakeholders that consent is not one-size-fits-all, and processes should be tailored ethically: e.g., using shorter, simpler assent forms for children, or protocols describing how consent will be obtained if a patient is unconscious at enrollment and later regains capacity.
Case Example: A sponsor implementing eConsent had an elderly participant who was not comfortable with tablets. The site printed the electronic form for her to read on paper, but then walked her through the same multimedia content on a tablet (e.g., showing a short informational video). She then signed the paper consent. The site scanned that into the eConsent system to keep the electronic record complete. This hybrid approach is perfectly acceptable – the priority is the participant’s understanding and voluntariness, not the method of signature. E6(R3) is flexible to such accommodations.
Thorough Documentation of the Consent Process
ICH E6 has always required that informed consent be documented (typically via a written, signed consent form). E6(R3) continues that and adds nuance to a few points:
- Consent Form Signatures: The guideline maintains that the participant (or their legally authorized representative) must sign and date the informed consent form (ICF) before any trial procedures. Additionally, the person who conducted the consent discussion (e.g., the investigator or designee) should also sign to attest that consent was given appropriately. This was in previous GCP as well, but E6(R3) explains this signature’s purpose: it’s a statement that, to the best of that person’s knowledge, the participant understood the information and consent was informed and voluntary. Investigators should ensure this counter-signature is not overlooked, even in electronic systems (which should capture the equivalent attestation).
- Recording Consent Discussions: While not mandated, it is considered good practice (strongly encouraged by many monitors and quality auditors) to record key aspects of the consent process in source notes. For instance, a brief note in the medical record like, “01-MAR-2025: Consent discussion held with patient via Zoom. Spent 45 minutes, went through all sections of ICF, patient asked about side effect risks and time commitment. All questions answered. Patient demonstrated understanding and signed eConsent with witness. Copy of ICF emailed to patient.” Such notes provide evidence that informed consent was truly a process, not just a formality. E6(R3) emphasizes that consent is more than just signing a document – it’s about communicating information and ensuring comprehension. Documenting the conversation (including any questions or concerns raised and clarified) shows regulators that the site took that obligation seriously.
- Version Control and Re-consent: In longer trials, new information may emerge (e.g., new risk findings, protocol amendments affecting participation) that require updating the consent form and re-consenting current participants. Under E6(R3), as before, sites must use IRB-approved updated forms and obtain consent from participants to continue, in a timely manner. What’s new is greater attention to not losing already collected data if a participant withdraws. The guideline suggests the protocol should specify what happens with data if someone withdraws consent (usually, data up to withdrawal can still be used). Therefore, consent forms might include language like, “If you withdraw consent, data collected up to that point will still be retained for the study, but no new data will be collected.” Ensure that re-consent processes are tracked — maintain a log of who has been re-consented on the new form. This can be as simple as adding an entry to each participant’s file noting “Consent version 2.0 discussed and signed on X date.” Remember that each consent version should be filed, and older versions should be archived (not discarded) with indication of their active dates. Good document management here demonstrates compliance with GCP.
- Consent in Decentralized Trials: With more trials having remote elements, consent might not happen in the investigator’s office. E6(R3) is fine with that, provided the process still meets all criteria. When using remote consent, sites should plan for providing a copy of the ICF to the participant (for example, via secure email or a patient portal) and allow ample opportunity for the person to ask questions – possibly scheduling a video call purely to go over the document. It’s also wise to have a method to confirm the participant’s identity and perhaps understanding (some eConsent systems include a short quiz on the study details to ensure comprehension, which the participant must complete before signing). While a quiz isn’t mandatory, it aligns with the spirit of truly informed consent and can be a helpful tool.
Upholding Ethics: Voluntariness and Ongoing Communication
Even as we innovate in how we obtain consent, the ethical bedrock remains unchanged. E6(R3) reinforces that informed consent is an ongoing, voluntary process. Participants should never be coerced or unduly influenced to participate or stay in a trial.
- Avoiding Therapeutic Misconception: One ethical challenge is participants misconstruing trial participation as personalized therapy. Consent discussions under E6(R3) should clearly convey the experimental nature of the treatment, the possibility of placebo or random assignment to different arms, and that their personal doctor will still care for them (if that’s the case). By being upfront and clear, we respect the participant’s autonomy. GCP also suggests explaining that they can withdraw at any time without penalty or loss of benefits, which is a statement always included in ICFs.
- Encouraging Questions: An investigator should actively invite the person to ask questions and take their time. E6(R3) doesn’t dictate how much time to give, but best practice is to not rush consent. Many sites give the form to the patient to take home and discuss with family, then sign at a later date if they choose. Some even have a policy that consent will be a two-step process: initial discussion, followed by a confirmation discussion a few days later, to ensure the person had time to consider. Such practices, though not required, demonstrate a thoughtful consent process appreciating the participant’s perspective.
- After Consent – Keeping Participants Informed: Informed consent doesn’t end with a signature. Throughout the trial, participants should be kept informed of any new information that might affect their willingness to continue. E6(R3) principle encourages transparency with participants, even to the point of suggesting investigators inform participants of the trial results afterward (where feasible and appropriate). For example, once a study is completed and results are public, many sponsors now provide a summary of the results to participants in lay language. While not a formal requirement, it’s considered good ethical practice and is mentioned in GCP as something investigators are encouraged to do (Section 2.9.3 of Annex 1). This helps maintain trust – participants gave their time; sharing what was learned is a way to honor that contribution.
Conclusion: Informed Consent as a Dynamic, Participant-Centered Process
Under ICH E6(R3), informed consent remains a fundamental requirement, but the approach to achieving truly informed consent is more participant-centered and flexible. The guideline pushes researchers to make consent forms understandable and not overly burdensome, thereby facilitating better comprehension. It also validates innovative methods like eConsent, which can improve reach and convenience (imagine enrolling a patient who lives 300 miles from the study site – with remote consent and monitoring, that becomes possible).
For investigators and sponsors, the onus is on ensuring that every participant fully understands what they are agreeing to and does so voluntarily. By simplifying consent language, engaging in genuine conversations (not monologues), and leveraging technology to enhance – not shortcut – understanding, we uphold the ethical imperatives of GCP.
From a regulatory standpoint, ethics committees reviewing trial applications under E6(R3) will scrutinize the consent process closely. They will look for concise forms, plans for non-traditional consent (if applicable), and measures to include special populations appropriately. A well-thought-out consent approach not only smooths the path to approval but more importantly leads to participants who are truly informed. Such participants are more likely to be comfortable and compliant during the trial, having entered with realistic expectations and trust in the research team.
In summary, informed consent in the E6(R3) era is about quality over quantity of information, flexibility in method without compromising ethics, and continuous respect for participant autonomy. By following these principles and the practical strategies outlined, clinical trial teams can ensure they meet regulatory requirements and, more importantly, honor the rights and dignity of the people who make clinical research possible.
References
- ICH Guideline for Good Clinical Practice E6(R3), Final Step-4 Guideline, Jan 6, 2025. [1]
- “The revamped Good Clinical Practice E6(R3) guideline: Profound changes in principles and practice,” Arun Bhatt, Perspectives in Clinical Research, 2023. [3]
- TransCelerate/ACRO’s E6(R3) Asset Library: tools on trial design, risk management, data governance. [5]
For those interested in gaining our Transcelerate Biopharma-certified courses, please enroll in our ICH GCP E6 R3 courses at https://www.whitehalltraining.com/
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