On August 15, 2023, the US Food and Drug Administration (FDA) finalized Informed Consent: Guidance for IRBs, Clinical Investigators, and Sponsors (final guidance). This document finalizes, with new examples and limited updates and modifications, the FDA’s draft guidance entitled Informed Consent Information Sheet: Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors, issued on July 15, 2014.
The final guidance supersedes the FDA’s guidance entitled A Guide to Informed Consent, issued in September 1998, and finalizes the 2014 draft guidance. The final guidance reflects the FDA’s current thinking and recommendations regarding informed consent and describes FDA regulatory requirements to help protect human subjects’ rights and welfare in clinical investigations.
In the nearly 10 years since the draft guidance was issued, the processes by which clinical trials and other human subjects research are conducted have evolved with technological advancements (e.g., platforms that can support decentralized research) and enhanced scientific knowledge (e.g., the ability to target therapies more closely to genetic variations). Based on clinical research experience during the last decade, including research conducted during the COVID-19 pandemic, the final guidance offers important clarifications and examples for institutional review boards (IRBs), investigators and sponsors as federal agencies continue efforts to harmonize regulations applicable to conducting human subjects research (detailed below).
However, further updates and clarifications are likely forthcoming as the FDA continues its notice-and-comment rulemaking process regarding informed consent requirements. That process could result in future changes—to the extent practicable and consistent with other statutory provisions—to align FDA informed consent requirements with revisions to the Federal Policy for the Protection of Human Subjects adopted by the US Department of Health and Human Services and several other federal departments and agencies. (That policy is known as the 2018 Common Rule, which we discussed in previous commentary.) The FDA cautions that it may amend the final guidance to reflect any such changes or to address new questions related to informed consent.
SUMMARY OF CONSENT PROCESS AND REGULATORY REQUIREMENTS FOR INFORMED CONSENT
The FDA opens the final guidance by explaining that informed consent involves more than just obtaining a subject’s signature on a consent form. It is a multi-step process that provides a potential research subject with sufficient information about a clinical investigation, facilitates the potential subject’s understanding of that information, and provides an adequate opportunity for the potential subject to ask questions and to carefully consider whether to participate. After the potential subject has voluntarily agreed and signed a consent form, the informed consent process also requires continued disclosure of new or additional information as the clinical investigation progresses, or as the enrolled subject or situation requires.
The FDA provides guidance regarding the requirements for informed consent set forth in FDA regulations at 21 CFR §§ 50.20 et seq., including a detailed discussion of the eight basic elements that must be provided to the potential subject and examples of situations in which additional elements should be included. The examples include situations involving vulnerable populations and situations that require disclosure of information about unforeseeable risks or consequences of withdrawal from the research. The guidance reiterates that where possible, individuals should be informed about the number of subjects participating in the trial. It also notes that the consent materials must include a statement about the availability of information about the investigation on ClinicalTrials.gov (to the extent sponsors and investigators determine that the investigation meets the definition of an “applicable clinical trial” set forth at 42 CFR § 11.10(a)).
The FDA concludes this section with guidance on documenting informed consent and situations where alternative methods of obtaining informed consent would be appropriate. The FDA clarifies that obtaining consent through electronic means may be an appropriate alternative to paper consent forms (citing to the FDA’s Guidance for Institutional Review Boards, Investigators, and Sponsors, Use of Electronic Informed Consent in Clinical Investigations). The FDA also notes that if the signed document cannot be retrieved (e.g., because the subject is in isolation due to an infectious disease) and electronic consent is not available, it is acceptable to instead include in the study records a photograph of the signed consent form along with an appropriate attestation. The attestation should be made by the person entering the photograph into the record, should state how the photograph was obtained, and should verify that the photograph depicts the informed consent form signed by the subject.
The FDA offers guidance on specific areas that IRBs should consider when reviewing and approving consent forms for compliance with FDA regulatory requirements, and to ensure that the informed consent process adequately protects the rights and welfare of subjects participating in the clinical investigation:
IRBs are responsible for reviewing all materials used in the informed consent process, not just the informed consent form itself. This means that the IRB should also review and approve recruitment materials and any other informational materials that will be provided to potential subjects for compliance with FDA requirements.
IRBs should review the adequacy and appropriateness of wording used in the informed consent form as well as its overall length and presentation to ensure that it is not too complex, legalistic or overwhelming to potential subjects.
IRBs must confirm that investigators will seek consent in ways that minimize the possibility of coercion and undue influence. They should confirm that consent will be appropriately documented and that any alternative methods for obtaining consent will accomplish the goals of the informed consent process. The FDA clarifies that certain administrative changes, such as correction of typographical or spelling errors or changes to telephone numbers, may be submitted at any time and do not require formal review and approval.
IRBs should establish procedures for the timely, efficient and effective review of new information about the research or changes in the clinical investigation. Investigators or sponsors should notify the IRB of new findings relevant to a subject’s decision to continue participation, approve revisions to the protocol or consent materials before they are initiated, implement an expedited review process for minor changes, and develop criteria for identifying revised consent forms to reduce the likelihood of continued use of a previously approved version. The FDA also provides new examples of scenarios in which additional information does not need to be provided, such as when the subject has completed active participation in the study or when the new information is unlikely to affect the subject’s decision to continue participating in the study.
CLINICAL INVESTIGATOR RESPONSIBILITIES
The FDA next offers guidance for investigators regarding their role and responsibilities in the informed consent process:
Investigators should notify the IRB of the consent process and provide copies of all patient- or subject-facing information regarding the investigation. Investigators should receive approval from the IRB prior to recruiting and enrolling subjects in the trial and should update the IRB and make necessary revisions to the process and information as the investigation progresses.
Investigators should only delegate the responsibility for obtaining informed consent to individuals who are qualified by education, training and experience; are knowledgeable about the specific clinical investigation; and have appropriate training and credentials to answer questions or address subjects’ concerns.
Investigators should consider whether to provide subjects with information related to financial relationships or interests that might have an effect on the investigation or interactions with subjects. Investigators should also consider other measures, such as involving another individual in the consent process who does not have a potential or actual conflict of interest or implementing independent monitoring of the consent process. Although the FDA directs these conflict-of-interest considerations to investigators, the FDA clarifies that the IRB has final responsibility for determining whether subjects should be provided with information regarding financial interests as part of the informed consent process.
The FDA provides guidance on sponsors’ role in the informed consent process. For example, the FDA clarifies the following issues:
If the sponsor provides investigators with a model consent form for adaption and use in the investigation, the sponsor should promptly provide the investigator with any revisions or modifications to the model form and work with the investigator to ensure that the IRB reviews and approves such modifications or revisions.
For multicenter clinical investigations reviewed by more than one IRB, the sponsor should share substantive modifications made by one local IRB with all other investigators and their IRBs. The sponsor should consider sharing this information using a modified model consent form. For multicenter investigations with a central IRB cooperating with local IRBs, the sponsor should forward substantive modifications to the central IRB.
Sponsors of medical device studies that will have personnel present during investigational procedures or follow-up visits or will otherwise engage in activities that will directly affect the subject, should describe those activities in the informed consent form.
FDA REVIEW CONSIDERATIONS
The guidance includes insights into the required submission of informed consent materials to the FDA in connection with a clinical investigation:
FDA regulations do not specifically require submission of consent materials in connection with an investigational new drug application (IND). However, the FDA generally requires consent forms associated with treatment INDs and protocols, as well as INDs conducted under exceptions from informed consent requirements in connection with emergency research, to be submitted for review.
The FDA considers several factors when determining whether to require the submission of materials in connection with other clinical investigations of drugs. These factors include unusual toxicity in nonclinical studies, vulnerable study populations, unusual study design, potential for serious risk to human subjects, and investigations that require subjects to forgo or delay effective treatment.
All forms and informational materials that will be provided to subjects in connection with clinical investigations of medical devices that require an investigational device exemption application must be submitted to the FDA for review.
The FDA reiterates that its review of informed consent forms is not a substitute for IRB review and approval.
FREQUENTLY ASKED QUESTIONS
The guidance closes with a series of new frequently asked questions (FAQs) related to the protection of human subjects. The FAQs address a variety of topics:
Enrollment of children, non-English speakers, individuals with low literacy and individuals with disabilities in clinical investigations
Individuals eligible to serve as a subject’s legally authorized representative
Electronic means of obtaining consent
Subject participation in multiple trials simultaneously (reiterating the FDA’s general discouragement as stated in the draft guidance, but acknowledging that co-enrollment may be appropriate in certain circumstances, such as rare disease studies that evaluate different aspects of a condition)
Subject withdrawal from studies or suspended or terminated studies
Whether informed consent is required to review patient records.
The final guidance does not address some of the novel issues associated with informed consent in a digital age, such as the following:
How privacy and security discussions related to data capture tools (such as smartphones) used during the clinical trial, but not studied as part of the clinical trial, should be incorporated into informed consent materials
How AI tools might facilitate the informed consent process (such as by answering subject questions).
The final guidance also declines to address the interplay of FDA informed consent requirements and HIPAA authorization requirements.