Inching Toward Harmonization: FDA Finalizes Rule on IRB Waiver of Informed Consent for Minimal Risk Studies

On December 21, 2023, the U.S. Food and Drug Administration (“FDA”) published a final rule to allow institutional review boards (“IRBs”) to waive or alter informed consent for certain clinical investigations that pose no more than minimal risk to human subjects and include appropriate safeguards to protect the rights, safety, and welfare of human subjects (the “Final Rule”).¹ The Final Rule follows a proposed rule issued in November 2018,² which we discussed in a previous Alert. It is one of several steps that FDA has taken to harmonize its requirements with those of the “Federal Policy for the Protection of Human Subjects,” known as the “Common Rule,”³ as required under the 21st Century Cures Act (the “Cures Act”) enacted in 2016.⁴ Other steps FDA has taken include publication of two proposed rules in September 2022 to harmonize FDA regulations pertaining to human subjects research and review of cooperative research by a single IRB with the Common Rule,⁵ which we discussed in an earlier Alert. To complete the harmonization process, which the Cures Act had required FDA to complete by December 13, 2019, FDA must still finalize these proposed rules. Additionally, FDA has said that it is also considering how certain other provisions in the Common Rule that are potentially relevant for FDA-regulated research, such as provisions on the posting of informed consent forms, broad consent, limited IRB review, exempt research, and public health surveillance activities, could be applied to FDA-regulated research.⁶

The Final Rule went into effect 30 days after publication, on January 22, 2024. Prior to the Final Rule’s effective date, IRBs were able to waive consent for minimal risk clinical research studies in accordance with FDA interim guidance published in 2017 (“Consent Waiver Guidance”),⁷ described in this Ropes & Gray Alert. That guidance announced FDA’s intention not to object to an IRB’s waiving or altering of the informed consent requirements for an FDA-regulated clinical investigation that presents no more than minimal risk and involves adequate human subjects protections. With the Final Rule now in effect, IRBs no longer need to rely on FDA’s nonbinding enforcement policy to waive or alter informed consent in appropriate circumstances.

In this Alert we describe the Final Rule’s requirements as well as key differences between the proposed and Final Rule.

Background

Both FDA regulations and the Common Rule have provisions to protect human research subjects, including requirements pertaining to IRB review and informed consent. FDA regulations govern clinical investigations (1) that are subject to FDA’s investigational product application requirements (either an investigational device exemption under 21 U.S.C. § 360j(g) or an investigational new drug application under 21 U.S.C. § 355(i)) or (2) the results of which will be submitted to FDA in support of a product application or held for inspection by FDA.⁸ Prior to FDA issuing this Final Rule, FDA’s regulations required investigators to obtain informed consent of clinical investigation participants, except (1) in certain life-threatening situations⁹ or (2) for emergency research.¹⁰

In contrast, the Common Rule applies to research conducted or supported by certain federal government departments or agencies that have adopted the Common Rule (e.g., the Environmental Protection Agency, Department of Health and Human Services, and National Science Foundation). Unlike FDA regulations, the Common Rule has long allowed IRBs to grant a waiver of informed consent for certain minimal risk research (e.g., observational research).

The difference in approach between FDA regulations and the Common Rule—on waiver of informed consent and in numerous other areas—has been a source of confusion, inefficiency, and frustration for researchers, particularly when research is subject both to the Common Rule and to FDA regulations. In an effort to promote scientific research and harmonize the Common Rule and FDA regulations, Congress included provisions addressing harmonization in the Cures Act in December 2016. In addition to mandating that FDA work to harmonize its regulations with the Common Rule where permitted by law, the Cures Act included a provision amending the Federal Food, Drug, and Cosmetic Act (“FDCA”) to permit IRB waiver of informed consent for research involving no more than minimal risk to human subjects, if appropriate safeguards are in place to protect the rights, safety, and welfare of subjects.¹¹ The Cures Act provision requires FDA to issue regulations to define and describe the conditions under which an IRB may waive informed consent for FDA-regulated minimal risk research activities.

Following passage of the Cures Act, in January 2017, the U.S. Department of Health and Human Services, together with 15 other federal departments and agencies, issued a final rule to revise and modernize the Common Rule (the “Revised Common Rule”).¹² The Revised Common Rule included four criteria for IRB waiver of informed consent that were included in the previous regulations and added a new fifth criterion: “If the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format.”¹³

Subsequently, FDA issued the Consent Waiver Guidance in July 2017 and, in November 2018, published the proposal to amend its regulations to permit IRBs to waive or alter informed consent requirements for certain minimal risk research. Both the Consent Waiver Guidance and proposed rule would permit an IRB to waive or alter informed consent if the first four criteria from the Common Rule were satisfied, but did not require the newer fifth criterion from the Revised Common Rule to be met.

The Final Rule

Under the Final Rule, FDA adds new section 21 C.F.R. § 50.22 to its regulations governing informed consent in FDA-regulated clinical investigations. The regulation permits an IRB to waive the requirement to obtain informed consent or approve an informed consent procedure that does not include or alters some of the required elements of informed consent set forth in § 50.25(a) and (b)¹⁴ if it finds and documents that the following five criteria are satisfied:

1. The clinical investigation involves no more than minimal risk to the subjects;
2. The clinical investigation could not practicably be carried out without the requested waiver or alteration;
3. If the clinical investigation involves using identifiable private information or identifiable biospecimens, the clinical investigation could not practicably be carried out without using such information or biospecimens in an identifiable format;
4. The waiver or alteration will not adversely affect the rights and welfare of the subjects; and
5. Whenever appropriate, the subjects or legally authorized representatives will be provided with additional pertinent information after participation.

This rule harmonizes FDA’s requirements for waiver or alteration of informed consent for minimal risk clinical investigations with the Revised Common Rule’s requirements, adopting identical criteria for waiver. Unlike the proposed rule and Consent Waiver Guidance, the Final Rule adopts the additional criterion that was added to the Revised Common Rule for waiver or alteration of informed consent. Thus, under the Final Rule, if the clinical investigation involves use of identifiable private information or identifiable biospecimens, informed consent requirements can be waived or altered only if the IRB determines that the investigation could not practicably be carried out without using the information or biospecimens in an identifiable format. In adopting this additional criterion, FDA explains that it intends to harmonize the waiver criteria with the Revised Common Rule, which it expects will reduce administrative burdens on IRBs and researchers and reduce research costs.¹⁵ This additional criterion focused on use of identifiable private information is also quite similar to that found in the HIPAA Privacy Rule for waivers of HIPAA authorization, which requires that to grant a waiver of HIPAA authorization for a research study, an IRB or privacy board must determine, among other things, that “the research could not practicably be conducted without access to and use of protected health information.”¹⁶

The rule is not otherwise substantively changed from the proposed rule. However, the preamble to the Final Rule provides some additional clarity on FDA’s interpretation of the criteria for waiver or alteration of informed consent. For example, FDA provides some comfort that the agency’s interpretation of the criteria for waiver generally is intended to align with how the criteria have been applied by IRBs under the Common Rule. FDA identifies the Secretary’s Advisory Committee on Human Research Protections (“SACHRP”) recommendations regarding the interpretation of the Common Rule criteria for waiver or alteration of informed consent as a resource for IRBs applying the FDA regulations¹⁷ and stresses repeatedly that the assessments under FDA’s new regulations will not be new to IRBs, which are experienced in applying the same criteria to research subject to the Common Rule.¹⁸

FDA also provides guidance in the preamble on its interpretation of when research would not be considered “practicable” without the requested waiver or alteration. Neither FDA’s regulations nor the Common Rule define the term “practicable,” leaving IRBs and researchers with some uncertainty in the application of this criterion. FDA had previously stated, in the preamble to the proposed rule, that obtaining consent may be impracticable if the research would be “unduly delayed” if it were restricted to consenting subjects.¹⁹ In responding to comments questioning whether “unduly delayed” was too low a bar, FDA points to SACHRP guidance explaining that practicability must be determined based on more than just considerations of convenience, cost, or speed, and that it interprets undue delay to mean “a delay in the initiation of a clinical investigation that is so lengthy as to raise ethical or scientific concerns given the benefit, or value, potentially gained by the research.”²⁰

FDA also addresses the issue of secondary research with leftover biospecimens, including the interaction of the Final Rule with existing FDA guidance addressing informed consent for in vitro diagnostic (“IVD”) device studies using non-identifiable leftover biospecimens.²¹ That guidance describes FDA’s intent to exercise enforcement discretion with respect to informed consent requirements for IVD investigations that use non-identifiable leftover human specimens and meet seven criteria. The criteria in that guidance overlap with, but are not identical to, the criteria in the Final Rule. For example, the guidance does not require IRBs to determine the research could not practicably be carried out without a waiver of informed consent or that it is minimal risk. FDA states in the preamble to the Final Rule that it believes that most IVD device investigations falling within the scope of the guidance also would satisfy the criteria for waiver of informed consent under the Final Rule. However, FDA acknowledges that this may not always be the case and clarifies that the IVD guidance will remain in place and cover such scenarios. The ultimate fate of the IVD guidance, though, and whether it may be withdrawn in the future, is unclear. FDA says only that the guidance will remain in place “at this time to help avoid potential disruption to IVD device investigations as IRBs gain experience implementing the new waiver provision in § 50.22 for FDA-regulated clinical investigations.”²²

Key Takeaways and What’s Next

The Final Rule provides a mechanism for researchers and companies engaged in minimal risk, FDA-regulated research to obtain a waiver or alteration of informed consent requirements. This may facilitate a range of research with the potential to advance the development of drugs and medical devices, including real-world data analyses intended to support submissions to the FDA and secondary research with biospecimens.

Additionally, the Final Rule is a significant, if partial, step in the harmonization of FDA human subjects research regulations with the Common Rule. We expect that this will create efficiencies and reduce confusion for researchers conducting and IRBs reviewing research under both the Common Rule and FDA regulations.

The Final Rule went into effect as of January 22, 2024. The rule applies to IRB review of any clinical investigation conducted on or after the effective date, including initial IRB approval or review of any changes to a previously approved clinical investigation. FDA has said that it plans to issue guidance to further assist IRBs in applying the criteria for waiver or alteration of informed consent requirements.

If you have any questions, please contact any member of Ropes & Gray’s FDA regulatory or health care practices or your usual Ropes & Gray advisor.