Since FDA’s issuance of the 2014 draft guidance, FDA has made significant investments in the clinical operations space to increase efficiency, improve diversity and inclusion, and embrace technological advances. These changes include innovations like platforms supporting decentralized research and the ability to target therapies based on genetic variations using machine learning and artificial intelligence. Drawing from the past decade of clinical research experience where the COVID-19 pandemic forced FDA to address the logistics of remote and fully decentralized trials, the final guidance provides essential clarifications and examples for institutional review boards (IRBs), investigators, and sponsors. For example, the guidance adds discussion of coercion and undue influence and provides clarity on electronic informed consent processes. The final guidance is part of a broader effort by federal agencies to harmonize regulations governing human subjects research.

The Informed Consent Process

Published on August 15, 2023, the 66-page final guidance underscores that “obtaining documentation of a subject’s informed consent is only part of the consent process.” Informed consent is not a one-time event; it’s an ongoing process, starting at the moment a patient is recruited, that involves providing comprehensive information about a clinical investigation to potential research subjects, ensuring their understanding, and offering an opportunity to ask questions and make an informed and voluntary decision about participation. Nor does the informed consent process end at enrollment. Participants should be informed of any changes to the study or new information that may affect their willingness to continue participating, such as when new safety information may require updates to likelihood of a specific adverse event occurring.

The final guidance also details the requirements for informed consent as outlined in FDA regulations at 21 CFR Part 50, Subpart B:

• Exceptions to Informed Consent. FDA regulation expressly provides limited exceptions to the informed consent requirement. The final guidance includes a footnote stating that FDA continues to exercise enforcement discretion with respect to the informed consent requirement for FDA-regulated in vitro diagnostic device investigations using human specimens that are not individually identifiable. FDA also discusses its proposed rule and guidance allowing IRBs to approve consent procedures that either omit certain elements or modify some or all of the components of informed consent with respect to clinical investigations with minimal risks. IRBs should note, however, that FDA’s approach to enforcement may shift if and when the Agency finalizes its proposed rule on waiver of informed consent.

• Coercion and Undue Influence. FDA clarifies its views around financial payments to research subjects and reimbursement for costs incurred through participation. For example, the final guidance adds language that says reimbursement for reasonable travel expenses and associated costs like parking and lodging would not raise issues related to coercion or undue influence of subjects. With respect to financial payment, FDA incorporates its 2018 Information Sheet, “Guidance for Institutional Review Boards and Clinical Investigators, Payment and Reimbursement to Research Subjects,” acknowledging that paying research subjects for their participation in a clinical trial is “a common, and, in general, acceptable practice.” At the same time, FDA comments that financial payment raises difficult questions that should be addressed by IRBs. To address these difficult questions, FDA instructs IRBs to review both the amount of payment and proposed method and timing of the disbursement and provides considerations for IRBs in reviewing proposed payments to trial participants to assure that they are not coercive or raise undue influence concerns.

• Understandable Language. Information given to a prospective research subject, including oral and written information, must be in language understandable to the prospective or their Legally Authorized Representative LAR. FDA defines “understandable” to mean information is in a language and at a comprehension level that the subjects can comprehend.

• Exculpatory Language. The consent process cannot allow a subject to waive any of their legal rights or release entities involved in the clinical investigation from liability for negligence. FDA updates this section with new examples of exculpatory and non-exculpatory language. FDA considers exculpatory language to comprise any language that “has the general effect of freeing or appearing to free an individual or an entity from malpractice, negligence, blame, fault, or guilt.”

The final guidance also discusses the eight basic elements that must be provided to potential subjects and provides examples of situations where additional elements may be necessary to obtain adequate informed consent, especially in cases involving vulnerable subject populations or unforeseeable risks. Below are a couple of key points pertaining to confidentiality of patient records and subject withdrawal from a study; the remaining elements of informed consent can be found both in FDA’s guidance document and in the associated regulations.

• Privacy Considerations. As with the draft guidance, FDA continues to reiterate the importance of privacy laws, including HIPAA. The informed consent process must include a description of the extent to which confidentiality of records identifying subjects will be maintained. The consent process should also disclose all entities and persons who may access clinical investigation records. FDA specifies that relevant entities for disclosure could include “the study sponsor, the research team, regulatory agencies, and/or ethics committee members.” FDA also underscores the importance for disclosing to subjects that FDA may inspect records and acknowledging that the agency does not promise absolute confidentiality with regard to records it inspects. The informed consent process must disclose that FDA may inspect records and should not state or imply that FDA needs subject permission to access records for inspection. FDA also notes that it may require subject names or other identifying information that could connect the subject with personal health information. While the agency will typically treat such information as confidential, it notes that it may be required to disclose this information to third parties. Thus, the agency cautions that the consent process should not promise absolute confidentiality with respect to records that may be inspected by FDA.

• Subject Withdrawal. Although not required under all circumstances, where “appropriate,” the consent process should describe the consequences of withdrawing from a clinical investigation and the procedure for terminating participation. Appropriate circumstances for disclosure of consequences related to withdrawal include when withdrawal may adversely affected the subject. Under those circumstances, the informed consent process needs to explain which withdrawal procedures are recommended for the participant’s safety and should specifically state why these procedures are important to their well-being.

  • The guidance adds that prospective subjects should be made aware of the number of visits and time required to participate in the study to help them evaluate whether they wish to participate. Further, it suggests counseling prospective subjects against participation if they do not anticipate staying in the study.

  • Where withdrawal must be disclosed in the informed consent process, the process must explain whether a subject who withdraws early will receive future study payments.

  • Similarly, the process must explain how data already collected will be handled after a subject withdraws. Under FDA regulations, data collected about subjects up to the date and time of withdrawal from clinical investigations must remain in the study database. FDA reiterates its position that removal of a withdrawn participant’s data would “undermine the scientific validity, and therefore the ethical integrity, of the research.” The agency recommends that subjects be advised in the informed consent document that data up to the date and time of their withdrawal will remain part of the database even after their withdrawal from the study.

In addition to describing the elements of informed consent, this section addresses how to document informed consent and offers guidance on situations where alternative methods for obtaining consent are appropriate. The discussion on when such alternative methods clearly draw on FDA’s experience with the COVID-19 pandemic. For example, FDA embraces the electronic consent as a suitable alternative to paper consent forms, incorporating language from its guidance entitled “Guidance for Institutional Review Boards, Investigators, and Sponsors, Use of Electronic Informed Consent in Clinical Investigations.” FDA also specifies that a photograph of the signed consent form, with an attestation, may be appropriate if electronic consent is not available and the signed document cannot otherwise be retrieved (e.g., because the subject is isolating due to a highly transmissible infectious disease).

Role of IRBs

FDA highlights the critical role the IRB plays in review and approving consent forms and the consent process for compliance with FDA regulations to safeguard the rights and welfare of human subjects. The guidance outlines specific areas to take into consideration when carrying out their responsibilities including:

• Reviewing all consent materials. FDA underscores that the regulatory requirement that IRBs review of all informed consent materials is not limited to form itself. IRBs should also review recruitment materials (e.g., advertisements) and other informational materials to ensure compliance with FDA regulations. Special emphasis is also placed on additional considerations for clinical investigations involving populations vulnerable to coercion or undue influence. FDA elaborates that in cases when an IRB regularly reviews clinical investigations that involve such populations, IRB membership for those investigations should “include individuals with knowledge about and/or experience working with such subjects.”

• Updates to consent materials. FDA contemplates that situations may arise during the clinical investigation that necessitate disclosure of new or additional information and/or modifications to consent forms. In such circumstances, IRBs should institute protocols for the “timely, efficient, and effective review of such new information or changes.” Although modifications should generally be reviewed and approved by the IRB prior to implementation, FDA clarifies that certain limited changes to an informed consent form that do not require IRB review and approval. In particular, the final guidance clarifies that administrative changes (e.g., typographical and spelling errors or changes in telephone numbers) “do not require formal review and approval,” though the modified form should be provided to the IRB.

• Translated consent materials. Regarding translated versions of consent materials, the new guidance specifies that IRBs can approve “reasonable procedures for ensuring that translations will be prepared by a qualified individual or entity, and that interpretation assistance is available.” This recommendation differs from the 2014 information sheet which recommended that IRBs review and approve “all English and non-English language versions of any consent documents.”

Role of Clinical Investigators

Under FDA regulations, clinical investigators are responsible for obtaining legally effective informed consent from subjects. FDA offers guidance to investigators on specific areas for consideration:

• Delegation. The final guidance clarifies that investigators may delegate the consent process to another party if certain protections are in place. For example, the person obtaining informed consent should “have the appropriate training and credentials” and be “knowledgeable about the study” to be able to effectively communicate information about the study and alternative course of treatment and answer questions. Nevertheless, FDA emphasizes its longstanding policy that, even when delegation occurs, the investigator retains ultimate responsibility for ensuring that legally valid informed consent is obtained for all subjects in accordance with FDA regulation.

• Financial Conflicts of Interest. FDA also comments that information about certain financial relationships and interests may be important to the subjects, as such financial relationships may affect subjects’ rights and welfare or willingness to participate. When financial relationships or interests exist, the guidance recommends that clinical investigators consider including in the informed consent form relevant information about the financial interest (e.g., information ownership of stock in the study sponsor or patents related to the investigational product), or implementing “special measures to modify the informed consent process” (e.g., having an individual without such conflicts involved in the consent process or using independent monitoring). Nevertheless, the Final Guidance explains that IRBs have the final responsibility of determining whether subjects should be provided with information regarding the source of funding, funding arrangements, or financial interests of parties involved in the clinical investigation as part of the informed consent process.

Role of Sponsors

The final guidance recognizes that sponsors often provide investigators with model consent forms and may receive comments from FDA on such model form. FDA advises sponsors to promptly provide investigators with any necessary modifications per FDA feedback and collaborate with investigators to ensure IRB review and approval of the modified consent form. This section also discusses specific considerations for sponsor with respect to multicenter clinical investigations and involvement of sponsor personnel in some medical device studies.

In the case of device studies, it is not uncommon for Sponsor personnel to be present during a surgical /medical procedure and/or follow-up visits to provide medical / clinical / technical support for the case or to document study-related information. If Sponsor personnel will be present or could directly affect the subject, it must be described in the informed consent form.

FDA Review

FDA generally requires sponsors submit consent materials in connection with a treatment investigational new drug application (IND), including INDs conducted under the emergency research exception to the consent requirement. The final guidance sheds light on the factors FDA considers when determining whether to require the submission for other clinical investigations of drugs. Factors include unusual toxicity identified in nonclinical studies, vulnerable subject population, unusual study design, and significant potential for serious risk to human subjects, and whether FDA has confidential or proprietary information not available to an IRB that affects the IRBs assessment of the adequacy of the informed consent, among others. It is important to note that it is the ultimate responsibility of the IRB to ensure compliance with informed consent requirements, even where FDA reviews the consent materials.

Where a medical device is under study and an investigational device exemption (IDE) application is required to be submitted to FDA, the informed consent materials and forms must be included in the IDE application. If FDA identifies deficiencies in the consent form, they must be corrected before the study may begin. Following IDE approval, if the IRB requires substantive changes to the informed consent document, i.e., changes that affect the rights, safety, or welfare of the subjects, the revised informed consent form must again be submitted to FDA for review and approval prior to implementing the changes to the document.

FAQ Section

The final guidance concludes with a 16-question FAQ section addressing FDA’s current thinking on a variety of common areas of interest.

• Topics include:

  • Whether informed consent is required to review medical records;

  • Special considerations for enrolling vulnerable subjects (children, non-English speakers, individuals with low literacy, and disabled individuals);

  • Electronic means of obtaining consent;

  • Subject participation in multiple clinical trials simultaneously;

  • How to handle data after subject withdrawal from a trial;

  • Informing subjects of suspended or terminated studies; and

  • The role of legally authorized representatives (LARs).

The FAQ section reorganizes and refreshes topics from the “Additional Considerations” section in the 2014 Information Sheet, and adds the topic on LARs. The new discussion on LAR recognizes that some cognitively impaired individuals “may be able to appoint an LAR, define the limits of their own research participation, or remain actively involved in the decision to enroll and remain enrolled in the research.” FDA emphasizes the importance of including such subjects in the informed consent process to the extent possible. With respect to obtaining informed consent from individuals physical or sensory disabilities, FDA clarifies that involvement of an LAR is not required unless otherwise provided in State or local law.