Harmonization is Here: What FDA’s Proposed Human Subject Protection Rules Mean for You

October 3, 2022
Firm Publication

On September 27, the Food and Drug Administration (FDA) issued two Notices of Proposed Rule Making that would harmonize the FDA’s human subject protection regulations with the Federal Policy for the Protection of Human Subjects (Common Rule). These proposed rules – and a draft guidance issued by the FDA on September 23 on the use of children in FDA-regulated clinical investigations – stem from a provision of the 21st Century Cures Act (Cures Act) that required the Department of Health and Human Services (HHS) to modernize the Common Rule, FDA regulations, and rules governing research with vulnerable populations. The Cures Act required modifications to be made by December 13, 2019.

While the FDA clearly missed the Cures Act deadline, HHS finalized significant revisions to the Common Rule in 2017, which became effective in 2018. The FDA’s human subject protection regulations apply, regardless of funding source, to any study under an Investigational New Drug (IND) application or Investigational Device Exemption (IDE), or if the study results are intended to be submitted to or held for inspection by the FDA. Because FDA-regulated research that is federally supported (for example, a clinical trial funded by the National Institutes of Health (NIH)) is subject to both the Common Rule and FDA regulations, the FDA issued guidance to address the inconsistencies between these regulations pending this Cures Act-required rulemaking.

This alert provides an overview of the proposed rules published last week. The first proposed rule would alter provisions governing institutional review boards (IRBs) and informed consent requirements (the Human Subjects Protection NPRM). The second one would impose a new requirement that all investigators or sites conducting an FDA-regulated study must rely on review and approval by a single IRB (Single IRB NPRM).

For convenience, we have created a redline showing the proposed changes.

Human Subjects Protection NPRM

The Human Subjects Protection NPRM (87 Fed. Reg. 58,733) would amend 21 C.F.R. Parts 50 (Protection of Human Subjects) and 56 (Institutional Review Boards), as well as one section of Part 812 (Investigational Device Exemptions), to:

  • Add new basic and additional elements of informed consent.
  • Revise the content, organization, and presentation of information included in the informed consent form and process to facilitate a prospective subject’s decision about whether to participate in the research.
  • Revise the IRB recordkeeping requirements for certain determinations related to the need for continuing review.
  • Add a provision that would allow IRBs to eliminate continuing review of research in certain circumstances.
  • Revise IDE requirements consistent with continuing review changes noted above.
  • Add or modify some definitions.

Note, however, that the Human Subjects Protection NPRM does not address provisions contained in a rule proposed in 2018, addressing IRB waiver or alteration of informed consent for clinical investigations that pose no more than minimal risk (83 Fed. Reg. 57,378) (2018 Proposed Rule). The 2018 Proposed Rule is not yet final, but the FDA noted in the preamble to the Human Subjects Protection NPRM that comments to the 2018 Proposed Rule are still under review. In the meantime, guidance issued in 2017 indicated that the FDA would exercise enforcement discretion with respect to IRBs waiving or altering informed consent in circumstances similar to when such waivers are appropriate under the Common Rule, something the FDA regulations do not currently give them the explicit authority to do.

New and Revised Definitions

The Human Subjects Protection NPRM proposes several technical and editorial revisions, including new and revised definitions that would help modernize the regulations in light of the changing research landscape. These changes include adding or revising the definitions of the following terms to align them with the Common Rule:

  • Legally authorized representative.
  • Written or in writing.
  • Private information.
  • Identifiable private information.
  • Identifiable biospecimen.

As discussed below, the terms “identifiable private information” and “identifiable biospecimen” also appear in the new proposed elements of informed consent and the proposed provisions regarding IRB continuing review. Additionally, these two newly defined terms may be relevant to the conditions on IRB waiver or alteration of informed consent if the FDA finalizes the 2018 Proposed Rule.

Updated Informed Consent Requirements

The Human Subjects Protection NPRM would impose new informed consent elements and requirements regarding how information is presented and organized in the informed consent document.

Although generally aiming to harmonize with the Common Rule, not all of the FDA’s proposed revisions to the informed consent elements are copied verbatim from the Common Rule. For example, the Common Rule requires subjects to be provided with one of two statements addressing whether or not the subject’s information and biospecimens could be de-identified and used for future research. The corresponding language proposed by the FDA is not limited to one of two statements but rather requires a “description of how information or biospecimens may be used for future research or distributed to another investigator for future research.” The FDA clarifies that using either of the Common Rule’s consent statements could be consistent with the Human Subjects Protection NPRM, but the FDA also notes that an investigator may also be required to provide “a description that conveys to subjects the possible future use of their identifiable biospecimens or information that may not be stripped of identifiers.”

The FDA is specifically requesting public comment on whether this proposal would provide adequate notice to potential subjects, whether the research community anticipates any challenges in implementing the new proposal, and whether the Common Rule’s language or any alternative approach would better inform subjects.

The FDA is not proposing to add a provision from the Common Rule allowing IRBs to approve a research proposal for which investigators obtain information or biospecimens without informed consent for screening or recruitment. The FDA states that “IRB review and informed consent would need to be obtained prior to initiation of any clinical screening procedure that is performed solely for the purpose of determining eligibility for a clinical investigation” (emphasis added). The reason for this omission is the FDA’s longstanding interpretation that some preparatory activities to a clinical investigation do not fall within the FDA’s definition of a “clinical investigation” and therefore do not require IRB review or informed consent under FDA’s regulations in the first place. Importantly, this approach differs from the Common Rule and the privacy regulations issued pursuant to the Health Insurance Portability and Accountability Act (HIPAA), both of which consider preparatory activities involving private information to be research, requiring IRB oversight under the Common Rule and a permissible basis under HIPAA. The FDA is specifically requesting public comment on whether its current policy adequately addresses screening, recruiting, or eligibility determinations for FDA-regulated clinical investigations or if the Common Rule provision would be useful for FDA-regulated clinical investigations.

To minimize disruptions to ongoing research, the FDA indicated that it would not enforce compliance with these new informed consent requirements for studies approved by an IRB before the effective date. The FDA seeks comments regarding the proposed effective date and implementation plan for ongoing research.

Waiver of Informed Consent Documentation

The FDA is proposing a new exception to allow an IRB to waive documentation of informed consent for a study that presents no more than minimal risk of harm to the subjects if the subjects or legally authorized representatives are members of a distinct cultural group or community in which signing forms is not the norm and there is an appropriate alternative mechanism for documenting that informed consent was obtained.

The FDA declined to include the Common Rule’s exception to the documentation requirement for situations in which the only record linking the subject and the research would be the informed consent document (in which case the principal risk would result from a breach of confidentiality). The FDA is seeking comments and examples regarding how this provision may be relevant to FDA-regulated research. While the FDA did not indicate why it believes this exception is not relevant to FDA-regulated research, the FDA’s thinking presumably relates to the existence of other records in clinical trials that can be linked to the subject that sometimes do not exist in surveys and other research that could be subject to the Common Rule but usually would not constitute a “clinical investigation” for purposes of FDA regulation.

IRB Composition and Approval of Research

The FDA is proposing to require that an IRB’s membership reflect a diversity of professional qualifications and other factors, including race, gender, and cultural background. IRBs reviewing federally-funded research must meet this requirement already. The Human Subjects Protection NPRM would also update language to describe persons considered vulnerable to coercion or undue influence as “children, prisoners, individuals with impaired decision-making capacity, and economically or educationally disadvantaged persons.” The provision currently lists “children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons.” To approve research involving any of these populations, an IRB must determine that additional safeguards have been included in the study to protect the rights and welfare of these subjects, and an IRB that regularly reviews research involving any of these populations must give consideration to including in its membership one or more individuals who are knowledgeable about and experienced in working with these populations.

IRB Continuing Review

The FDA is proposing to add exceptions to the IRB continuing review requirements for the following two types of research unless an IRB determines otherwise:

  • Research that has progressed to the point that it involves only data analysis, including analysis of identifiable private information or identifiable biospecimens and/or accessing follow-up clinical data from procedures that subjects would undergo as part of clinical care.
  • Research that involves only a long-term follow-up phase during which subjects are monitored as they undergo clinical care for their medical condition or disease by their healthcare provider. During this continued follow-up phase, information regarding long-term clinical outcomes may be obtained through accessing clinical data generated during clinical care.

The FDA’s revisions to IRB continuing review requirements again depart from the revised Common Rule by omitting two continuing review exceptions contained in the Common Rule. One of these exceptions is related to the “limited IRB review” procedure introduced by the revised Common Rule; however, the FDA noted that it would continue to consider how this might apply to FDA-regulated research. The other exception is for research eligible for expedited review (i.e., research involving no more than minimal risk to human subjects). The FDA explained that requiring continuing review even for minimal risk FDA-regulated clinical investigations would provide meaningful protections to human subjects because the analysis of risks to subjects receiving a drug or device may change based on adverse events that do not rise to the level of “unanticipated problems involving risks to human subjects” that would otherwise be reported to the IRB.

These proposed revisions to the continuing review requirements require corresponding updates to progress reporting requirements under the IDE regulations for device studies (21 C.F.R. Part 812), which are also included in the Human Subjects Protection NPRM.

Effective Date

Except for the delayed effectiveness of the informed consent requirements noted above, the FDA proposes that any final rule be effective 180 days from publication in the Federal Register. The new exceptions to IRB continuing review would apply to ongoing FDA-regulated studies as of the effective date of the final rule.

Single IRB NPRM

Absent an exception, the FDA’s proposed Single IRB NPRM (87 Fed. Reg. 58,752) would require U.S.-based institutions to rely on review and approval by a single IRB for the portion of the research conducted in the U.S. The rule would apply to any institution or investigator participating in FDA-regulated cooperative (i.e., multicenter) research. The revised Common Rule already requires the use of a single IRB for federally-funded cooperative research, and NIH policy imposes a similar requirement for research funded by the NIH.

Currently, FDA regulations permit, but do not require, an institution or investigator participating in a multicenter study to rely on the review of any IRB that meets FDA requirements. In our experience, study sponsors often designate a central IRB to streamline IRB review and prevent consistent outcomes and delays that can occur when several IRBs review the same study. Some institutions, however, may prefer to have their own IRB review a study even when the sponsor is using a central IRB because they believe another IRB does not have sufficient local context for the institution, and may not meet the same standards as the institution’s IRB, or is not subject to adequate institutional oversight. Some institutions’ IRBs also currently perform functions of an institutional human research protection program that are not required to be performed by an IRB.

In a departure from what the revised Common Rule requires, the FDA is not proposing that a specific party involved in the research select the IRB when a single IRB process is used, but for practical reasons, this will usually be the study sponsor. The sponsor is already required to identify the reviewing IRB in the IND application (21 C.F.R. § 312.23(a)(6)(iii)(b)) or an IDE application (21 C.F.R. § 812.20(b)(6)) submitted to FDA.

Reliance Agreements

The FDA proposes requiring documentation of an institution’s reliance on an external IRB that would describe the responsibilities each entity will undertake to ensure compliance with FDA regulations. Examples of documentation that would meet this requirement include a written agreement between the institution and the IRB, an institution-wide policy directive providing the allocation of responsibilities between the institution and an external IRB, or a research protocol section that provides that allocation. IRB authorization or reliance agreements are not new; even before they were required by the revised Common Rule, the Office for Human Research Protections (OHRP) expected them to be in place for research subject to an OHRP-approved Federalwide Assurance (FWA) and had developed a basic template for institutions to use as a resource.

Many research institutions and some commercial IRBs have signed a Master Common Reciprocal IRB Authorization Agreement through SMART IRB, linked here, but many community hospitals and most physician practices that conduct industry-sponsored research have not. SMART IRB is also only available to institutions with an FWA, which organizations and investigators that have only ever conducted privately-funded research will not ordinarily have. This is likely to represent a significant burden on IRBs and on institutions and investigators that do not currently have Common Rule-compliant reliance documentation in place with their reviewing IRBs.

Proposed Exceptions

Because of the burdens involved in setting up and documenting IRB reliance arrangements, the FDA also proposes specific exceptions for circumstances in which it believes mandating a single IRB may not be justified:

  • Cooperative research for which more than a single IRB review is required by law, including trial law passed by the official governing body of an American Indian or Alaska Native tribe. This exception also exists under the revised Common Rule.
  • Cooperative research involving a highly specialized FDA-regulated medical product for which unique, localized expertise is required. For example, experts in a particular medical product may only exist in geographically dispersed locations, and an IRB in that area would likely most efficiently fulfill the duties of an IRB. However, the FDA expects that this exception will be used only rarely.
  • Cooperative research on drugs exempt from IND regulations under 21 C.F.R. § 312.2(b). IND-exempt drug studies are generally lower risk; therefore, increased efficiencies leading to earlier investigations would generally not provide the benefit of bringing new drugs or new uses of drugs to market sooner.
  • Cooperative research on medical devices that meets the abbreviated IDE requirements under 21 C.F.R. § 812.2(b) or requirements for exempted device investigations under 21 C.F.R. § 812.2(c). This proposed exemption would encompass research that presents lower risks to subjects and in some instances, may not involve a therapeutic intervention or invasive procedure, including research that is not focused on bringing new devices to market.

Note that the use of an exception would not be mandatory if it applied. Thus, institutions and investigators conducting these studies could still choose to rely on a single IRB even though the research met a permissible exception to the general rule.

The FDA declined to propose adopting a second exception found in the revised Common Rule, which covers situations where a federal agency determines and documents that using a single IRB is inappropriate for a particular context. The FDA is nevertheless seeking comment on whether it should add an analogous exception and on the following additional questions:

  • Whether it is appropriate to include an exception for cooperative research for which the use of a single IRB is unable to meet the needs of specific populations such as minority groups or pregnant women.
  • Whether it is appropriate to include an exception for cooperative research with a small number of investigational sites.
  • The impact of situations where a federally-conducted or supported FDA-regulated clinical investigation would qualify for an exception from a single IRB but would not qualify for an exception under the revised Common Rule (or vice versa).
  • Whether there are any unique challenges in using a single IRB for FDA-regulated cooperative research that could not be addressed by the FDA’s proposed exceptions.
Effective Date

The FDA proposes that the new rule be effective one year after the final rule is published in the Federal Register. Further, the final rule would only apply to cooperative research approved by an IRB on or after the proposed effective date. Ongoing research that an IRB approved before the proposed effective date would have the option – but not be required – to use a single IRB.

Conclusion

If enacted, these proposed rules would affect all clinical trial sponsors, all research sites conducting clinical trials, and all IRBs reviewing clinical trials. Affected parties should be particularly cognizant of how the proposed changes differ from the Common Rule. It is important to note that these proposed changes do not address all of the revised Common Rule provisions, such as provisions for posting informed consent forms, broad consent, limited IRB review, exempt research, public health surveillance activities, and IRB review of research involving de-identified specimens (something the FDA regulations currently require in certain circumstances but the Common Rule does not).

Individuals and organizations engaged in FDA-regulated research and IRBs reviewing that research should also anticipate additional proposals from the FDA to further harmonize its regulations with the revised Common Rule.

Comments to both proposed rules are due by November 28, 2022, and can be submitted here for the Human Subjects Protection NPRM and here for the Single IRB NPRM.

Please contact the authors if you have any questions about these proposed revisions or if you would like assistance submitting a comment to either of the proposed rules.