On August 15, 2023, FDA published a final guidance entitled, “Informed Consent, Guidance for IRBs (Institutional Review Boards), Clinical Investigators, and Sponsors.” This final guidance supersedes the September 1998 guidance entitled “A Guide to Informed Consent” and replaces the July 2014 draft guidance “Informed Consent Information Sheet.” This final guidance does not include any major new concepts but builds on the foundation established in these previous documents. Of note, the FDA has not yet harmonized with the 2018 changes to the Common Rule that were implemented under 45 CFR 46 but plans to do so in the near future 1. Consequently, the final guidance does not include any of the changes to the informed consent regulations that were implemented under the 2018 Common Rule.
The final guidance references where the differences exist between FDA regulations and the 2018 Common Rule, where there are plans to update the regulations and how IRBs, investigators and sponsors might navigate the differences between the two processes in the meantime (see guidance entitled Impact of Certain Provisions of the Revised Common Rule on FDA-Regulated Clinical Investigations for more on this topic). In particular, FDA has not yet harmonized on the waiver or alteration of informed consent requirements for minimal risk research to align with requirements under 45 CFR 46.116(f)(3); however, does note that FDA will not object to the IRB approving a consent procedure that does not include, or that alters, some or all of the elements of informed consent, as long as the specified additional requirements are satisfied. Further information on this process can be found in the guidance entitled, IRB Waiver or Alteration of Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to Human Subjects
Most IRBs are familiar with the content of the 2014 draft guidance, “Informed Consent Information Sheet.” The final Informed Consent guidance duplicates the categories in the 2014 draft guidance with the exception that “Additional Considerations” have been rearranged under a section entitled “Frequently Asked Questions.” The summary here focuses on the changes or additions included in the final guidance when compared to the 2014 draft guidance.
Summary of the Consent Process
The final guidance emphasizes that the informed consent process, which involves not only signing the consent form, but also providing subjects with adequate information to make an informed decision about study participation, starts with the recruitment of subjects and continues throughout the study. The information included in recruitment material should be limited to the minimal information needed for a prospective subject to determine interest and eligibility. Recruitment materials should be consistent with the informed consent document. Additionally, the final guidance notes that providing new information to subjects as it emerges is an important aspect of the informed consent process. Augmented information on processes for informing subjects of new information during study participation is included in the final guidance.
General Requirements for Informed Consent
The final guidance includes a statement that FDA does not consider reimbursement for reasonable travel expenses and associated costs to raise issues of coercion and undue influence. Reimbursement for other expenses is considered an acceptable practice and may be considered by IRBs on a case-by-case basis; payment for participation should be just and fair. However, any payments should not be considered a benefit to justify the risks of the research when IRBs evaluate whether the risk to patients is justified in relation to the anticipated benefit as per 21 CFR 56.111(a)(2).2
Basic Elements of Informed Consent
Regarding the basic element of consent requiring a description of risks and discomforts, the final guidance has been updated to include a statement that “where relevant, participants should also be made aware of the possibility of unintended disclosures of private information and be provided with an explanation of measures to protect a subject’s privacy and data and limitations to those measures.” This further emphasizes the requirement under 21 CFR 56.111(a)(7) that IRBs are required to determine, where appropriate, that there are adequate provisions to protect the privacy of subjects and to maintain confidentiality of data.
Regarding the description of benefits, the final guidance restates that information about the investigational agent and control should include relevant information about the potential benefits of each. The final guidance adds, for studies involving a comparison of an investigational agent to standard of care, it may be acceptable to generally describe the benefits of the standard of care in the informed consent form and provide more detailed information on the benefits of the standard of care during the consent discussion. This point follows a general trend in the final guidance to find ways to streamline the consent form and process. Although not directly addressed in the guidance, this approach should also apply to the description of potential risks as well as the potential benefits for the investigational agent, control, and standard of care based on what information is known at the time consent is obtained.
The language on what is required to be described in the consent form regarding alternatives has been softened. The 2014 draft guidance stated that a description of the risks and benefits for appropriate alternative procedures or courses on treatments were required to be disclosed. The final guidance no longer requires this, but instead recommends that these alternatives be disclosed as part of the consent discussion but not necessarily included in the informed consent document. This change will allow IRBs to make qualitative decisions on what is necessary to include in this section to adequately inform participants without an undue burden on the information required to be included in the consent form.
Although not directly discussed in the body of the final guidance, changes to the application of Certificates of Confidentiality (CoC) are pertinent as they relate to participant confidentiality. The 21st Century Cures Act amended the statutes relating to the issuance of CoCs. The statute broadened the protections for research participants by specifically prohibiting holders of CoCs from disclosing identifiable, private information unless specific exemptions apply. The Cures Act also required that CoCs be issued for any federally funded research that collects or uses identifiable, sensitive information. Sponsors and sponsor investigators should be aware that they may request a discretionary CoC for FDA regulated research from the FDA. FDA will review the request and determine if the CoC will be granted for the research.3 Sponsors and sponsor investigators may want to consider a CoC for research that may collect particularly sensitive information.
Additional Elements of Consent
If a statement on unforeseeable risks to subjects (or to the embryo or fetus) is considered appropriate for the informed consent document, the final guidance recommends that “sponsors may want to consider whether appropriate birth control measures and notifying the investigator of pregnancy should be included in the protocol and addressed in the informed consent document.”
Under additional costs to subjects, the final guidance emphasizes that the informed consent document should include sufficient information on the protocol requirements and time commitment so that the participant can appreciate how much time may be needed away from work, childcare, or elder care and how much of the cost will be borne by the sponsor or paid by the subject.
Under consequences of the subject’s decision to withdraw from the study, the final guidance discusses that subjects may need to be counseled that they should not participate in the trial if they do not foresee staying in the study. Subjects should also be made aware of the number of visits and time required to ensure they are committed to completing the research. Encouraging potential study participants to consider the commitment and costs associated with the research in advance of study participation might help with study retention once participants are enrolled in the trial.
The section on significant new findings to subjects has been expanded to include additional situations that may impact a subject’s willingness to continue in the study. These may include the results from interim analyses, information on alternative procedures or treatments that come available during the trial, efficacy results from other trials using the investigational product or information on the effectiveness of a comparator. If the information is significant, the IRB should consider whether patients in the trial should be contacted to determine whether the new information might impact their desire to stay in the trial. The final guidance further expounds on this topic under “Frequently Asked Questions.”
Documentation of Informed Consent
The final guidance provides an alternate way of providing a signed consent form, for example if a participant is in strict isolation for a highly transmissible infectious disease and electronic consent is not available. A photographic image of the signed consent form can be retained in the records. The person entering the photograph into the medical record needs to state how the photograph was obtained and that it is a photograph of the informed consent signed by the subject.
A discussion on the use of short forms notes that because a witness is needed when a short form is used, and a written summary of the verbally supplied informed consent discussion must be supplied, which is generally the English version of the long form, that using a short form may not ease or expedite the informed consent process compared to the use of a long form.
IRB Responsibilities
Additional language has been added to state that the IRB should inquire who will conduct the consent discussion and what procedures will be followed. If other than a face-to-face discussion is proposed, such as by telephone, the IRB should consider whether the procedures will impact effective communication. Alternative methods for obtaining informed consent might be of concern if the clinical trial includes complex procedures or risks that might be difficult to comprehend.
Updates to consent forms for typographical or spelling errors and changes to telephone numbers do not need formal IRB review, but the updated documents need to be sent to the IRB, so the IRB has current copies of the documents.
The final guidance notes that other visual aids, in addition to pictures and diagrams, may be used to improve understanding of the research during the consent process.
Clinical Investigator Responsibilities
The final guidance states that although the clinical investigator should consider whether financial relationships and interests may impact the informed consent process, the IRB has the final responsibility in determining whether subjects should be provided with information regarding the source of funding, funding arrangement or financial interests of parties involved in the clinical investigation as part of the informed consent process.
Sponsor Responsibilities
For multicenter clinical investigations, the final guidance expands on the concept that if local review of a consent form results in significant changes, that those changes should be shared with all the investigators or IRBs and if a central IRB is involved local changes should be shared with the central IRB. Not noted in the previous draft guidance but required by regulation (21 CFR 812.35(a)) is that these changes must be shared with the FDA for medical devices that require an IDE (Investigational Device Exemption).
The final guidance notes that for some medical device studies a sponsor representative or field engineer may be present during the procedure and/or follow-up visits. If this occurs, or sponsor activities directly affect the subject, these activities should be described in the consent form.
Frequently Asked Questions
Much of what is in this section was found in the “Additional Considerations” section of the 2014 draft “Informed Consent Information Sheet.” Clarifications and additions are discussed below.
For “What are some considerations for enrolling a child in a clinical investigation?” a section on mature minors and emancipated minors is described. In these situations, depending on the laws of the local jurisdiction where the study is being conducted, a minor may no longer meet the definition of a child4 and may be able to consent for themselves without parental or guardian permission.
Under “Are there any additional protections required when enrolling children who are wards of the state?” the enrollment of children in clinical investigations who are wards of the state, as described under 21 CFR 50.56, is clarified in the final guidance. An advocate is required for clinical investigations conducted under 21 CFR 50.53 and 50.54, where other conditions are met, but is not required for clinical investigations under 21 CFR 50.51 and 50.52. However, FDA recommends an advocate be appointed for all research conducted with wards of the state. The advocate should not be associated with the clinical investigation, investigator, or guardian organization except in their role as an advocate.
Under “What process should be followed when the enrollment of subjects who do not understand English is not expected?” the process for use of a translated short form and English long form clarifies that the witness does not need to be fluent in the language but must have sufficient proficiency to attest that the information was presented orally to the potential participant and also notes that the witness, if possible, should not be related to the subject. Further emphasis is added that whenever subjects who do not understand English are enrolled in a study that appropriate interpreter services should be available to the subject throughout the research.
For “What should be considered when enrolling subjects with physical or sensory disabilities?” it is noted that unless required by state or local law that a LAR (legally authorized representative) is not required to be involved in the informed consent process or to sign the consent form. The participant can signal consent as is consistent with applicable law.
A section has been added on who can serve as a LAR and what their role is in a section entitled ‘Who can serve as a legally authorized representative (LAR) and what is their role?” This section discusses that the legal authority as to who can serve as a LAR is established by State and local law. IRBs, investigators and/or sponsors may need to consult with legal counsel or their institution to determine who may serve as a LAR. A LAR may be included as part of the consent process, but individuals with impaired consent capacity should be included in the consent process to the extent that they are capable of participating. An individual capable of consent at the beginning of a study but expected to experience cognitive decline over time may elect to designate someone who can serve as LAR once they can no longer consent for themselves.
A section, “How can informed consent be obtained through electronic methods?” has been added to note that FDA supports the use of informed consent through electronic methods, noting that the consent process may employ interactive methods that may facilitate comprehension, “may promote timely entry of any electronic informed consent into a study database and facilitate collection of informed consent from remote locations.” The final guidance refers the reader to the specific FDA guidance entitled, “Use of Electronic Informed Consent – Questions and Answers.”
The question “Can a subject participate in more than one clinical investigation simultaneously?” includes a new consideration that, in some cases, it may be appropriate for a subject to enroll in more than one trial. A few examples are given, such as rare disease studies that are evaluating different aspects of the disease and participating in one study does not impact the other study or for appropriately designed studies where a companion device needed for the safe and effective use of the drug may be tested alongside the clinical investigation of a novel drug. The section also adds that the risks of participating in more than one clinical trial should be discussed during the consent process, but these risks do not necessarily need to be included in the consent form.
The final guidance adds that the FDA supports supplying subjects with aggregate study results (“Should subjects be informed of aggregate study results at the completion of a trial?)” As previously noted in the 2014 draft guidance, for clinical trials that are required to register in www.ClinicalTrials.gov, aggregate summary results will be posted, however sponsors and investigators can voluntarily register trials and submit summary results for trials even if they are not required to register the trial. What has been added to the final guidance is an explanation that the regulations do not address IRB review of aggregate results. The final guidance recommends that when there is a plan to return aggregate results at the initiation of the trial or if a decision is made to share results after initial approval but while the study is still open with the IRB, the IRB should review the plan on how results will be shared. If the plan to share aggregate results is made after the study is closed with the IRB, the IRB does not need to review the sponsor’s plan to share the results with the subject.
The final guidance includes an expanded section on informing subjects of new information that may impact their willingness to continue to participate in the research under a question entitled “How should subjects be informed of new information that may affect their willingness to continue participation in the research?” The IRB has significant flexibility in determining the procedures that the IRB believes are appropriate to affirm the subject’s willingness to continue in the research. If the consent form is revised, the IRB may determine that currently enrolled subjects should also be informed and if a revised informed consent or an addendum are appropriate. In situations where a revised informed consent is used to provide new information to subjects and document willingness to continue in the trial, the FDA recommends that the investigator prepare a summary of the changes to the informed consent document to reduce any confusion about any of the changes and aid in presenting the new information. FDA notes that subjects currently participating in the trial do not need to be informed if the new information is unlikely to affect their decision to continue to participate and subjects who have completed a trial do not need to be informed of new information unless the new information relates to a risk that may still be of concern after study participation. However, the IRB has the option to recommend that the investigator provide the summary prepared for the reconsent discussion to all subjects currently and previously enrolled, for their awareness.
Conclusion
The final FDA guidance, “Informed Consent, Guidance for IRBs, Clinical Investigators, and Sponsors,” does not include any significant new concepts but does expound on some old ones to address contemporary issues, such as the utility of electronic informed consent, subject payment, protecting confidentiality and details on how to address new findings in research. It is a substantial document that will serve as a valuable resource for IRBs, investigators and sponsors when considering the informed consent process and developing and reviewing the informed consent document.
[1] On September 28, 2022, FDA issued proposed rules to harmonize certain provisions of 21 CFR parts 50 and 56 with the 2018 Common Rule with some exceptions to maintain consistency with other FDA statutory provisions.
[2] FDA Information Sheet, Payment and Reimbursement to Research Subjects Guidance for Institutional Review Boards and Clinical Investigators, January 2018
[3] Certificates of Confidentiality, Guidance for Sponsors, Sponsor-Investigators, Researchers, Industry, and Food and Drug Administration Staff
[4] 21 CFR 50.3(o) defines children as “persons who have not attained the legal age for consent to treatments or procedures involved in clinical investigations, under the applicable law of the jurisdiction in which the clinical investigation will be conducted.”