Informed Consent in Clinical Research: Compliance Risks and Best Practices
Informed consent is a foundational pillar of clinical research, ensuring participants fully understand the scope, risks, and benefits of a study before enrollment. Despite its well-established importance, it remains one of the most cited issues in regulatory inspections, often leading to compliance risks and protocol deviations.
With increased regulatory scrutiny and the transition to ICH E6(R3), informed consent processes require more rigorous oversight, enhanced documentation, and improved participant understanding. This article examines key compliance risks, recent FDA enforcement actions, and best practices to strengthen informed consent procedures.
With increased regulatory scrutiny and the transition to ICH E6(R3), informed consent processes require more rigorous oversight, enhanced documentation, and improved participant understanding. This article examines key compliance risks, recent FDA enforcement actions, and best practices to strengthen informed consent procedures.
REGULATORY TRENDS AND COMPLIANCE RISKS
High-risk area for violations
Regulatory bodies, including FDA and EMA, consistently report informed consent deficiencies as a leading
cause of inspection findings. Common compliance gaps include:
• Failure to obtain legally valid consent (e.g., missing signatures, improper delegation).
• Lack of participant comprehension despite signed consent forms.
• Outdated or inconsistent documentation across trial sites.
Recent FDA Enforcement Action: Key Lessons
A recent FDA warning letter highlighted critical informed consent violations in pediatric research, where minors were enrolled with consent forms signed by unauthorized individuals—siblings and extended family members instead of legal guardians. This case underscores key regulatory expectations:
✔ Legal accountability: Every informed consent form must be signed by an authorized individual, without exceptions.
✔ Participant comprehension: A signature alone does not confirm true understanding—sites must ensure meaningful consent discussions.
✔ Ongoing training & audits: Compliance failures often stem from procedural drift. Regular site training
and internal audits are essential.
📄 Read the full FDA warning letter here: FDA Warning Letter
HOW ICH E6(R3) IMPACTS INFORMED CONSENT
The transition from ICH E6(R2) to E6(R3) reinforces key expectations for patient protection and data integrity. While the fundamental principles remain unchanged, the updated guidelines emphasize:
1.Reinforced Ethical Principle
According to Principle 2 of ICH E6(R3), “informed consent is an integral feature of the ethical conduct of a trial.” Participation must be voluntary, and the process must ensure that participants (or their legally acceptable representatives) are thoroughly informed. This foundational principle reaffirms that consent is not merely a signed document but a comprehensive process aimed at enabling individuals to make an informed decision about participating in a trial.
2.Investigator Responsibilities
Under section 2.1, investigators are required to obtain and document freely given informed consent prior
to any trial-related procedures. When a participant cannot provide consent themselves, the legally acceptable representative may do so, acting in the participant’s best interest. Additionally, minors must assent in accordance with their level of understanding and in compliance with local regulations (see ICH E11(R1)).
Practical Implication: Investigators need SOPs (Standard Operating Procedures) that clearly define steps for obtaining consent—especially for vulnerable populations such as minors or those with impaired decision-making capacity.
3. Clarity, Conciseness, and Participant Understanding
Sections 2.2 and 2.8.1(b) emphasize that consent forms and discussions should be clear, concise, and easy for
a layperson to understand. Overly complex or lengthy materials can hinder true informed consent. It is now explicitly stated that potential participants should be able to evaluate the trial’s benefits, risks, and burdens without wading through unnecessary technical jargon.
Practical Implication: Simplify language, use bullet points or infographics, and ensure local reading-level requirements are met. Regularly update ICF (Informed Consent Form) templates and educational materials
to reflect evolving protocols and to maintain user-friendliness.
4. Use of Technology and Remote Consent
A major advancement in E6(R3) is the explicit acknowledgment of remote consenting options in section 2.8.1(d). Sponsors and sites may use electronic or remote methods to facilitate the informed consent process, provided they maintain data integrity, confirm participant identity (section 2.8.1(e)), and ensure participants can fully understand the trial’s requirements.
Practical Implication: Adopting eConsent platforms can help standardize the consent experience, provide
real-time version control, and create detailed audit trails. However, sites must also offer non-electronic alternatives when participants lack technological access or prefer a paper-based method.
5. Proportionality and Risk-Based Approaches
Although not stated under a single heading, the proportionality principle in ICH E6(R3) weaves through various sections. The rigor and oversight for the consent process should align with the trial’s complexity and risk profile. Informed consent should remain robust, but investigators can tailor the methods used—such as interactive electronic forms, educational videos, or smaller group discussions—based on participant needs and the nature
of the study.
Practical Implication: Complex, high-risk trials may require more comprehensive consent discussions and
closer oversight, whereas lower-risk or observational studies may implement briefer, yet still compliant, consent procedures.
6. Ongoing Communication and Re-consent
Section 2.8.2 mandates timely updates to participants if any new information emerges that could affect their willingness to continue. Investigators must document this communication, and if the new information significantly impacts the risk-benefit assessment, re-consent may be necessary. Revised informed consent materials must receive IRB/IEC approval prior to use.
Practical Implication: Implement a robust tracking system for protocol amendments, safety updates, and changes in risk profiles. Ensure participants quickly receive updates—especially in fast-moving trials—so they can reaffirm
or reconsider their participation.
7. Site Oversight and Monitoring
Stronger site oversight is emphasized in ICH E6(R3). Sponsors and CROs must incorporate risk-based monitoring strategies to ensure the informed consent process is being conducted properly at all participating sites.
This includes verifying compliance with consent procedures, checking documentation, and ensuring no undue influence or coercion occurs (sections 2.8.3–2.8.5).
Practical Implication: Sponsors should perform periodic onsite or remote quality сhecks of consent documentation. Centralized monitoring tools can flag deviations in real time, helping sites correct issues quickly and maintain
a standardized consent experience across multiple locations.
High-risk area for violations
Regulatory bodies, including FDA and EMA, consistently report informed consent deficiencies as a leading
cause of inspection findings. Common compliance gaps include:
• Failure to obtain legally valid consent (e.g., missing signatures, improper delegation).
• Lack of participant comprehension despite signed consent forms.
• Outdated or inconsistent documentation across trial sites.
Recent FDA Enforcement Action: Key Lessons
A recent FDA warning letter highlighted critical informed consent violations in pediatric research, where minors were enrolled with consent forms signed by unauthorized individuals—siblings and extended family members instead of legal guardians. This case underscores key regulatory expectations:
✔ Legal accountability: Every informed consent form must be signed by an authorized individual, without exceptions.
✔ Participant comprehension: A signature alone does not confirm true understanding—sites must ensure meaningful consent discussions.
✔ Ongoing training & audits: Compliance failures often stem from procedural drift. Regular site training
and internal audits are essential.
📄 Read the full FDA warning letter here: FDA Warning Letter
HOW ICH E6(R3) IMPACTS INFORMED CONSENT
The transition from ICH E6(R2) to E6(R3) reinforces key expectations for patient protection and data integrity. While the fundamental principles remain unchanged, the updated guidelines emphasize:
1.Reinforced Ethical Principle
According to Principle 2 of ICH E6(R3), “informed consent is an integral feature of the ethical conduct of a trial.” Participation must be voluntary, and the process must ensure that participants (or their legally acceptable representatives) are thoroughly informed. This foundational principle reaffirms that consent is not merely a signed document but a comprehensive process aimed at enabling individuals to make an informed decision about participating in a trial.
2.Investigator Responsibilities
Under section 2.1, investigators are required to obtain and document freely given informed consent prior
to any trial-related procedures. When a participant cannot provide consent themselves, the legally acceptable representative may do so, acting in the participant’s best interest. Additionally, minors must assent in accordance with their level of understanding and in compliance with local regulations (see ICH E11(R1)).
Practical Implication: Investigators need SOPs (Standard Operating Procedures) that clearly define steps for obtaining consent—especially for vulnerable populations such as minors or those with impaired decision-making capacity.
3. Clarity, Conciseness, and Participant Understanding
Sections 2.2 and 2.8.1(b) emphasize that consent forms and discussions should be clear, concise, and easy for
a layperson to understand. Overly complex or lengthy materials can hinder true informed consent. It is now explicitly stated that potential participants should be able to evaluate the trial’s benefits, risks, and burdens without wading through unnecessary technical jargon.
Practical Implication: Simplify language, use bullet points or infographics, and ensure local reading-level requirements are met. Regularly update ICF (Informed Consent Form) templates and educational materials
to reflect evolving protocols and to maintain user-friendliness.
4. Use of Technology and Remote Consent
A major advancement in E6(R3) is the explicit acknowledgment of remote consenting options in section 2.8.1(d). Sponsors and sites may use electronic or remote methods to facilitate the informed consent process, provided they maintain data integrity, confirm participant identity (section 2.8.1(e)), and ensure participants can fully understand the trial’s requirements.
Practical Implication: Adopting eConsent platforms can help standardize the consent experience, provide
real-time version control, and create detailed audit trails. However, sites must also offer non-electronic alternatives when participants lack technological access or prefer a paper-based method.
5. Proportionality and Risk-Based Approaches
Although not stated under a single heading, the proportionality principle in ICH E6(R3) weaves through various sections. The rigor and oversight for the consent process should align with the trial’s complexity and risk profile. Informed consent should remain robust, but investigators can tailor the methods used—such as interactive electronic forms, educational videos, or smaller group discussions—based on participant needs and the nature
of the study.
Practical Implication: Complex, high-risk trials may require more comprehensive consent discussions and
closer oversight, whereas lower-risk or observational studies may implement briefer, yet still compliant, consent procedures.
6. Ongoing Communication and Re-consent
Section 2.8.2 mandates timely updates to participants if any new information emerges that could affect their willingness to continue. Investigators must document this communication, and if the new information significantly impacts the risk-benefit assessment, re-consent may be necessary. Revised informed consent materials must receive IRB/IEC approval prior to use.
Practical Implication: Implement a robust tracking system for protocol amendments, safety updates, and changes in risk profiles. Ensure participants quickly receive updates—especially in fast-moving trials—so they can reaffirm
or reconsider their participation.
7. Site Oversight and Monitoring
Stronger site oversight is emphasized in ICH E6(R3). Sponsors and CROs must incorporate risk-based monitoring strategies to ensure the informed consent process is being conducted properly at all participating sites.
This includes verifying compliance with consent procedures, checking documentation, and ensuring no undue influence or coercion occurs (sections 2.8.3–2.8.5).
Practical Implication: Sponsors should perform periodic onsite or remote quality сhecks of consent documentation. Centralized monitoring tools can flag deviations in real time, helping sites correct issues quickly and maintain
a standardized consent experience across multiple locations.
Conclusion
Maintaining compliance with informed consent regulations is not just about avoiding regulatory findings—it is fundamental to ethical clinical research. As ICH E6(R3) introduces refinements, organizations must take proactive measures to strengthen their processes, embrace technology-driven solutions, and ensure that informed consent is truly informed.
📢 How is your organization preparing for the upcoming transition to ICH E6(R3)? Which aspects of the updated informed consent requirements do you find most significant? Share your thoughts in the comments!
📢 How is your organization preparing for the upcoming transition to ICH E6(R3)? Which aspects of the updated informed consent requirements do you find most significant? Share your thoughts in the comments!