To comply with the 21st Century Cures Act,1 the Food and Drug Administration (FDA or USFDA) has released two Notices of Proposed Rulemaking (NPRMs). NPRMs are the initial public notice of a proposed change to federal regulations. These two NPRMs are intended to harmonize the FDA institutional review board (IRB) and informed consent regulations with the Federal Policy for the Protection of Human Subjects (the “Common Rule”) to the extent possible.
The Common Rule was revised in 2018, and the FDA’s two recent NPRMs will harmonize the FDA regulations with the majority of those 2018 revisions. The Common Rule has been adopted by 20 federal agencies and applies to research that is conducted or supported by those agencies. One NPRM describes a potential requirement for multi-site research that is under FDA oversight to use a single IRB for the review of all study sites.2 The second NPRM describes changes to FDA regulations to harmonize with the Common Rule regarding informed consent requirements, among other things.3
This paper will discuss the new proposed informed consent NPRM.
In the FDA NPRM on Protection of Human Subjects and IRBs,3 it is the proposed harmonization with the Common Rule requirements for informed consent documents that will most likely affect research sponsors. Like the Common Rule, the proposed rule would require:
The “key information” section, to be placed at the start of the consent form, should provide a summary of the most important information that may lead someone to decide whether to participate in a trial. Decisions about what needs to be included here may be subjective, and the information will likely vary for each study based on the study and the study population. The purpose of the study, overall duration, major study requirements (e.g., monthly study visits for 3 years) and most significant risks are often appropriate to include, but there may be additonal important information. For example, if the study population involves young adults but the study drug may cause birth defects, then the need to avoid pregnancy for years may be significant. If developing resistance to the study drug is possible or if the study drug could limit future treatment options, then that may be important information to include. It will be essential for clinical team members who understand the study drugs and the study population to think critically and carefully about what key information to include.
While no specific guidance around the content of a key information section have been provided by regulatory agencies, the Secretary’s Advisory Committee on Human Subject Research (SACHRP) provided some recommendations,4 based on the Common Rule requirement in 2018. Other organizations may also provide some advice; for example, WCG IRB recommends that the key information section be 1/10 the length of the overall informed consent document but not more than 3 pages even if the consent is longer than 30 pages.
FDA also includes language that reinforces general principles of informed consent, as stated below:
FDA is proposing to include three additional elements of informed consent, which have already been included in the revised Common Rule, at sections 21 CFR 50.25(b)(7), (8), and (9).
- Section 50.25(b)(7) would require a statement that the subject’s biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit.
- Section 50.25(b)(8) would require a statement on whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions.
- Section 50.25(b)(9) pertains to research involving biospecimens and would require that subjects be informed whether the research will (if known), or might, include whole genome sequencing (WGS).3
FDA has also proposed to clarify in 21 CFR 50.27 that electronic informed consent is acceptable by adding a parenthetical statement to that eeffect; it would state,
Consent Elements Pertaining to Future Use of Research Specimens
FDA has also proposed not harmonizing with two elements of informed consent that were added to the Common Rule in the 2018 revisions; instead, FDA proposed different requirements. The first of these involves the Common Rule requirement to provide subjects with information regarding the future use of data for additional research purposes.
The Common Rule language at 45 CFR 46.116(b)(9) reads as follows:
However, FDA’s proposed new regulatory language at 21 CFR 50.25(a)(9) reads as follows:
The goal of this new element in the Common Rule was to let subjects know whether their information and specimens might be used for further research without obtaining additional future consent. FDA has attempted to improve the language by making it more open ended, but it could lead to several unintended consequences.
FDA’s proposed language at 21 CFR 50.25(a)(9) is more open-ended and, in many cases, will be difficult for the sponsor or investigator drafting the consent form to complete. Future research with information or biospecimens is often not planned when writing the original protocol and informed consent form, so there would be no information to provide to the subject.
FDA’s proposed language could result in IRBs and other parties interpreting the failure to describe future secondary research in the consent form as a prohibition on secondary research without consent, which would restrict the ability to perform that research under the current regulations. Parties in research may also be concerned that the conduct of secondary research without consent could be a finding in an FDA inspection if it was not explicitly described in the consent form. Therefore, it may reduce their willingness to conduct such research, which could result in the loss of an opportunity for valuable additional information from studies.
IRBs, institutions, and investigators involved in the review and conduct of federally-funded research have already adopted many of these provisions in 2018 in the Common Rule, and these new informed consent requirements will have less impact. Commercial sponsors and investigators who do not participate in federally-funded research will have to update consent form templates and other documents (required element checklists, etc). Some sponsors of FDA regulated research may have already encountered the key information section requirement, if working with a local IRB that applies Common Rule requirements to all research.
The timeline for adoption of these proposed changes to the FDA regulations is unclear; it could take several months or even several years. However, forward-thinking sponsors and researchers may want to start updating their informed consent template now, as none of these changes are contradicted by current regulations. The only change WCG IRB does not recommend making now is the change regarding future use of specimens; because of the challenges described above and the potential for the requirement to change, it may be best to wait until the final regulations are released.
- 21st Century Cures Act, Section 1002, Public Law 114-255. https://www.govinfo.gov/app/details/PLAW-114publ255
- Notice of Proposed Rulemaking: Institutional Review Boards; Cooperative Research (87 FR 58752) https://www.federalregister.gov/documents/2022/09/28/2022-21089/institutional-review-boards-cooperative-research
- Notice of Proposed Rulemaking: Protection of Human Subjects and Institutional Review Boards (87 FR 58733) https://www.federalregister.gov/documents/2022/11/14/2022-24689/protection-of-human-subjects-and-institutional-review-boards-and-institutional-review-boards
- SACHRP Commentary on the New “Key Information” Informed Consent Requirements, October 17, 2018. https://www.hhs.gov/ohrp/sachrp-committee/recommendations/attachment-c-november-13-2018/index.html
- Code of Federal Regulations Title 45 46.116 https://www.ecfr. gov/current/title-45/subtitle A/subchapter-A/part-46/subpart-A/ section-46.116
Note: While the term “research participant” or “research volunteer” is generally preferred, US federal regulations use “research subject”, so this paper discussing the proposed regulations has used the regulatory terminology.
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