Earlier this month, the U.S. Food and Drug Administration (“FDA”) issued a draft guidance, “Key Information and Facilitating Understanding in Informed Consent”, with notable implications for clinical trial sponsors, investigators, and Institutional Review Boards.[i] The guidance provides suggestions on which topics of information should be included in the key information section of an informed consent as well as how information can be presented and formatted in an informed consent to aid prospective subjects’ understanding of a clinical trial.

Background

The U.S. Department of Health and Human Services (“HHS”) sets forth regulations for the protection of human subjects in research in 45 CFR part 46, of which Subpart A is referred to as the “Common Rule.” The Common Rule generally requires that researchers obtain informed consent from individuals who participate in research. In 2017, HHS announced revisions to the Common Rule, including (1) requiring that the informed consent “begin with a concise and focused presentation of the key information that is most likely to assist a prospective subject or legally authorized representative in understanding the reasons why one might or might not want to participate in the research” and (2) that the informed consent as a whole be presented in a way which “facilitates the prospective subject’s or legally authorized representative’s understanding of the reasons why one might or might not want to participate.”[ii]

FDA also sets forth regulations for the protection of human subjects in 21 CFR parts 50 and 56, and the 21^st Century Cures Act directs the Secretary of HHS to harmonize differences between HHS’s and FDA’s human subject protection regulations. Consequently, on September 28, 2022, FDA issued a proposed rule (the “Proposed Rule”) to align 21 CFR parts 50 and 56 with the revised Common Rule.[iii] The comment period for the Proposed Rule closed in December 2022, but the final rule has not yet been published. This guidance provides further clarification on requirements related to the key information section and presentation of information in the informed consent in an organized and understandable manner.

Key Information Section

The key information section of an informed consent should provide the key information which is most likely to assist a prospective subject in understanding the reasons why they may or may not want to participate in the research.[iv] This section can guide discussions between a prospective subject and investigator on the risks and benefits of trial participation. FDA recommends that the key information section generally be no more than a few pages, and also encourages flexibility and innovation in this section to improve clarity and increase prospective subjects’ understanding of consent information.

The key information section should begin with an introductive framing statement. Whether information is considered “key” to be included in this section should be evaluated from the perspective of potential subjects, and the inclusion of particular consent elements can vary based on the specifics of a trial. FDA notes the importance of highlighting risk information and appropriate repetition of key information throughout the informed consent, such as through page numbers or hyperlinks.

Additionally, FDA provides guidance on the following topics to incorporate in the key understanding section, including its content and formatting:

1. Voluntary Participation and Right to Discontinue Participation. FDA recommends including a statement that a decision to not participate or discontinue participation in a study would not result in any penalty or loss of benefit, or adversely affect a subject’s relationship with or medical care received from health care providers.
2. Purpose of the Research, Expected Duration, and Procedures To Be Followed. FDA suggests inclusion of a description of why the research is being conducted and why the prospective subject is being asked to participate in a way which helps a prospective subject understand why they may or may not want to participate. Although descriptions of specific study design details may vary, the expected duration of participation, major procedures involved, investigational medical product and its marketing authorization status, and any experimental procedures can be included.
3. Reasonably Foreseeable Risks and Discomforts. FDA notes the importance of disclosing serious risks and discomforts, and suggests it be included on the first page. Key risks should be described first. Additionally, the risks and discomforts associated with an investigational medical product or other investigational procedure should be delineated from those associated with other research interventions or procedures.
4. Reasonably Expected Benefits. Any lack of benefits should be clearly stated, and for clinical research, the difference between clinical research and clinical care should be noted. Benefits should be described in a manner which is accurate and not overly optimistic, simple, and straightforward. FDA also recommends only the benefits which result from the research itself should be considered.
5. Appropriate Alternative Procedures. The purpose of this section is to increase awareness of alternatives in order to bolster personal choice. FDA recommends describing the risks and benefits associated with alternatives in a clear and concise manner.
6. Compensation and Medical Treatments for Research-Related Injuries. FDA notes inclusion of this information may be especially important when costs related to the treatment of research-related injuries will not be compensated.
7. Costs Related to Subject Participation. Costs which may be incurred by a prospective subject or whether their insurance will be charged should be disclosed. Alternatively, reimbursement for study-related expenses and incentives for participation can also be included.

Facilitating Understanding

FDA not only provides recommendations on how informed consent forms as a whole can be organized and presented to facilitate understanding, but also provides a sample key information section that follows FDA’s new formatting recommendations. In the key information section, FDA proposes the use of “bubbles” (rounded boxes with defined borders), each conveying a discrete piece of information, in order to aid comprehension. In order to make an informed consent easier to read overall, FDA also suggests the use of multiple columns, bullet points, and white space. The key information section and informed consent should include sufficient detail and be thoughtfully organized. A tiered approach to document organization, as well as a table of contents and page numbers to cross-reference related topics, can also improve organization. Finally, the language in an informed consent should be understandable and tailored to the needs and characteristics of the prospective subject population.

Key Takeaways

This guidance identifies and recommends a significant amount of information which may need to be newly incorporated into an informed consent or reorganized in a manner which facilitates understanding for prospective subjects. Furthermore, FDA has suggested novel formatting and organizational methods, such as the use of “bubbles.” The release of the guidance suggests that the Proposed Rule may soon be finalized, which would codify requirements related to the key information section. Consequently, clinical trial sponsors, investigators, and Institutional Review Boards should revisit their informed consents sooner rather than later to not only ensure a key information section is appropriately included, and also evaluate whether any formatting updates may be necessary to comply with FDA rulemaking and regulations.

The guidance also emphasizes the importance of the key information section in assisting prospective subjects’ decision to participate in a clinical trial as well as guiding discussions between potential research subjects and investigators. Clinical trial sponsors may need to evaluate their informed consent process, including its timing and suitability for its relevant subject population. Furthermore, to the extent a clinical trial sponsor relies on external companies or third-party vendors for patient recruitment, further conversations between the parties may be needed to ensure prospective subjects provide informed consent at the appropriate time in the recruitment process and in accordance with regulatory requirements and guidance. 

FOOTNOTES

[i] FDA, Draft Guidance, “Key Information and Facilitating Informed Consent: Guidance for Sponsors, Investigators, and Institutional Review Boards,” available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/key-information-and-facilitating-understanding-informed-consent-guidance-sponsors-investigators-and.

[ii] 45 CFR 46.116(a)(5)(i) – (ii).

[iii] 87 FR 58733, 58749 (September 28, 2022).

[iv] 45 CFR 46.116(a)(5)(i); 87 FR 58733.