Four years after the Department of Health and Human Services revised the Common Rule, the FDA has proposed regulations to harmonize its rules with the revised Common Rule (87 Fed. Reg. 58733).

The proposed rule, if finalized, would amend 21 C.F.R. Parts 50 and Part 56 to:

• revise the content, organization, and presentation of information included in the informed consent form and process to aid a prospective subject's decision about whether to participate in the research;
• add new basic and additional elements of informed consent;
• add a provision that would allow institutional review boards (IRBs) to eliminate continuing review of research in certain circumstances;
• require U.S. institutions participating in cooperative research to rely on approval by a single IRB;
• revise the IRB recordkeeping requirements for certain determinations related to the need for continuing review and for research that takes place at an institution in which IRB oversight is conducted by an IRB that is not operated by the institution; and
• add or modify definitions.

The agency also proposed revising 21 C.F.R. Part 812 regarding progress reports submitted by investigators and sponsors to a reviewing IRB for consistency with the revisions in 21 C.F.R. Part 56 to the continuing review process.

“FDA believes that these proposed changes, if finalized, would help ensure clarity and enhance both human subject protection and the IRB review process,” the agency said in announcing the proposed rules. “In addition, harmonizing with the revised Common Rule would reduce regulatory burden for IRBs, sponsors, and investigators. ”

The FDA said the “primary quantifiable benefit of the proposed rule is a decreased time burden to IRBs, investigators, and sponsors of clinical trials from increased harmonization with the revised Common Rule. Quantifiable costs include the development of informed consent documents and additional recordkeeping burdens. The estimated annualized cost savings of the proposed rule range from approximately $22 to $103 million in 2018 dollars, with a central estimate of approximately $43 million.”

The agency noted the proposed rule does not address all of the changes contained in the revised Common Rule as the FDA addressed some of the revisions in a 2018 proposed rule on IRB waiver or alteration of informed consent for minimal risk clinical investigations.

In addition, the agency is “considering how other provisions of the revised Common Rule that are potentially relevant to FDA-regulated research,” such as how posting of informed consent forms, broad consent, limited IRB review, exempt research and public health surveillance activities, could be applied to FDA-regulated research. “FDA plans to take additional steps to harmonize FDA's regulations with the revised Common Rule, to the extent practicable and consistent with statutory provisions,” the agency said.

Specific Changes Detailed

The FDA proposes to amend the general requirements for informed consent under 21 C.F.R. §50.20 to harmonize with the revised Common Rule at 45 C.F.R. §46.116(a)(1) through (6). “These requirements address the content, organization, and presentation of information included in the consent form and process to facilitate a prospective subject's decision about whether to participate in the research,” the notice said.

The FDA would add a new paragraph that “would clarify that the prospective subject or the subject's legally authorized representative must be provided with the information that a reasonable person would want to have to make an informed decision about whether to participate and be given an opportunity to discuss that information.”

The agency also proposes to require that 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 (LAR) in understanding the reasons why the subject might or might not want to participate in the research, and that the information be organized and presented in a way that aids the subject's or LAR's comprehension.

Under elements of informed consent, the FDA would require the provision of additional information to potential subjects about the possible future use of their information or biospecimens. “This information will help subjects make informed decisions about whether to participate in a particular clinical investigation,” the agency said.

The FDA's proposed new element also would require a description of how information or biospecimens may be used for future research or distributed to another investigator for future research. The agency noted that while the FDA's proposed rule is not exactly the same as the revised Common Rule regulation, “the research community would be able to develop informed consent forms and processes that comply with both sets of regulations.”

The agency added the FDA's proposal “is intended to incorporate flexibility as to the description that an investigator would provide to each subject or the legally authorized representative to help ensure that subjects are informed regarding possible future uses of information and biospecimens collected from their participation in a clinical investigation as the ways in which information and biospecimens are used relevant to FDA-regulated products continue to evolve.”

The agency requested public comment on “whether the proposed new basic element of informed consent would provide adequate notice to potential subjects regarding the possible future research use of their information and biospecimens or whether the Common Rule's provision at 45 C.F.R. §46.116(b)(9) would better inform potential subjects about the possible future use of their information and biospecimens in research. We further request public comment on whether the research community anticipates challenges in implementing FDA's proposed new element and whether an alternative approach could lessen such challenges.”

The FDA also proposed adding three new elements of informed consent that 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;
• require a statement on whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions; and
• require that subjects be informed whether the research will (if known), or might, include whole genome sequencing.

The FDA also would revise 21 C.F.R. §50.25(d) and (e) by adding a reference to tribal law passed by the official governing body of an American Indian or Alaska Native tribe, to clarify that references to federal, state or local law are intended to include tribal law.

As to the documentation of informed consent, the FDA proposed adding a parenthetical to 21 C.F.R. §50.27(a) to clarify that consent forms in an electronic format are an acceptable format and revising 21 C.F.R. §50.27(b)(2) to require that the key information required by 21 C.F.R. §50.20 be presented first when using a short form written informed consent.

“These changes are being proposed to better inform potential subjects about participation in a clinical investigation, and to harmonize with the revised Common Rule,” the agency said.

The FDA noted it is not proposing to add the new provision in the revised Common Rule (45 C.F.R. §46.116(g)), which allows IRBs to approve a research proposal for which investigators obtain information or biospecimens without an individual's informed consent for the purpose of screening, recruiting, or determining eligibility of the prospective human subject or LAR if either of the following conditions are met: (1) the investigator will obtain information through oral or written communication with the prospective subject or LAR or (2) the investigator will obtain identifiable private information or identifiable biospecimens by accessing records or stored identifiable biospecimens.

“FDA's longstanding policy on preparatory activities to a clinical investigation is that some specific activities are not considered to fall within the definition of a clinical investigation, and therefore do not require IRB review or informed consent under FDA's regulations,” the agency said in explaining its decision.

The notice requested comment on whether FDA's current policy adequately addresses screening, recruiting, or determining eligibility for an FDA-regulated clinical investigation, or if including the revised Common Rule provision would be useful for FDA-regulated clinical investigations.

Single IRB Review Proposed

The FDA is proposing new regulatory text to require that any institution located in the United States participating in FDA-regulated cooperative research rely on approval by a single IRB for that portion of the research that is conducted in the United States.

The agency noted the revised Common Rule requires the reviewing IRB to be identified by the federal department or agency supporting or conducting the research, or to be proposed by the lead institution subject to the acceptance of the federal department or agency supporting the research.

“It is not practicable for FDA to propose this same requirement because, unlike research subject to the revised Common Rule, most of the research that FDA regulates is not conducted or supported by FDA or by any federal department or agency,” the notice said. “FDA's existing regulations do not require that a specific party involved in the research select the IRB when a single IRB process is used, and we are unaware of difficulties in selecting the IRB that warrant requiring the single IRB always to be identified by a particular party for all FDA-regulated research. Because FDA is not proposing to require that a particular party identify the single IRB, there would be no conflict for FDA-regulated research that is also subject to the revised Common Rule requirement that the single IRB be identified by the federal department or agency supporting or conducting the research or proposed by the lead institution subject to the acceptance of the federal department or agency supporting the research.”

FDA is proposing the same exception to the single IRB review requirements as under 45 C.F.R. §46.114(b)(2)(i) for cooperative research for which more than single IRB review is required by law (including tribal law).

In addition, the FDA found it “impracticable” to adopt an exception for situations in which FDA determines and documents that the use of a single IRB is not appropriate for the particular context. “Unlike review of a research grant application that would be submitted to a federal department or agency for approval, certain FDA-regulated research does not require a submission to FDA or other interaction with FDA before it begins,” the notice said.

“If FDA were to require such research to obtain FDA's determination and documentation that single IRB review is not appropriate, it would add administrative burden and delay the initiation of research, contrary to the goals of this proposed rule.”

The FDA requested comment on whether the agency should consider adding this exception “to help address potential challenges to use of a single IRB review model for FDA-regulated cooperative research.”

The agency is also proposing an exception from the use of single IRB review for research involving a highly specialized FDA-regulated medical product for which unique, localized expertise is required.

“For example, for certain highly specialized FDA-regulated medical products, expertise in the use of the product may be limited to only a few specialists at geographically dispersed locations. In such cases, the investigators, research staff, and IRBs associated with the investigational sites would have the critical knowledge and training relevant to the product, and therefore, these IRBs would have the capability to most efficiently conduct initial review and oversee the research, while maintaining appropriate human subject protections,” the FDA said.

“We believe that mandating the use of single IRB review could be an obstacle to initiating important research when the localized expertise is readily available, but none of the IRBs associated with the investigational sites can serve as the single IRB of record. FDA believes that this proposed criterion for exception from use of single IRB review would be met in such a case, although we expect that such exceptions would be rare occurrences,” the agency said.

The FDA also is proposing an exception from mandatory use of single IRB review for research on drugs that is exempt from the requirements for an IND application under 21 C.F.R. §312.2(b). “Such studies are generally lower risk clinical investigations of products that are lawfully marketed. Unlike clinical investigations that are conducted under the IND requirements, increased efficiencies leading to earlier initiation of clinical investigations exempt from the IND requirements generally would not provide the benefit of bringing new drugs or new uses of drugs to patients sooner,” the FDA said.

The agency also is proposing an exception from the requirement for single IRB review for research on medical devices that meets the abbreviated requirements under 21 C.F.R. §812.2(b) or that meets the requirements for exempted investigations under 21 C.F.R. §812.2(c), to the extent the exempted investigation would be subject to 21 C.F.R. Part 56.

“This proposed exception would encompass research that presents a lower risk to subjects and, in certain instances, may not involve a therapeutic intervention or invasive procedure (e.g., studies of certain diagnostic devices),” the notice said. “The proposed exception would also encompass research that is not focused on bringing new devices to the market for patients. Therefore, the initial administrative burden of establishing cooperative review agreements may not be offset by the anticipated benefits of single IRB review efficiencies, such as improvement in the review and handling of safety reports and faster initiation of research that facilitates the development of new medical products.”

The FDA noted that the agency had considered recommendations provided by the Secretary's Advisory Committee on Human Research Protections regarding additional categories of research that would be potentially appropriate for exception from the requirement to use a single IRB.

The agency wants public comment on several of these potential categories for exception:

• Is it appropriate to include an exception for cooperative research for which use of a single IRB is unable to meet the needs of specific populations. “Such an exception might apply, for example, to research that involves recruiting members of a distinct patient population or community (e.g., cultural, religious) for which the local perspective is particularly important if the single IRB of record is unable to obtain sufficient
• supplemental information to consider that community's needs,” the notice said.
• Would a single IRB of record generally be able to supplement its members' knowledge and experience with additional information or expertise to account for these situations?
• Are there examples of FDA-regulated research for which these circumstances would apply, and is there any data on the frequency of how often this situation may occur?
• Would an exception from single IRB review be warranted for a multisite study with a small number of sites?
• What are the benefits and burdens for a multisite study with a small number of sites, and what should the appropriate threshold be for the number of sites involved?
• Is there any specific data on the relationship between the number of sites and the value of single IRB review.

In addition, the “FDA recognizes that situations may arise in which a federally conducted or supported FDA-regulated clinical investigation would qualify for an exception from single IRB review under this proposed rule but would not qualify for an exception determination issued by a Common Rule department or agency.”

The agency wants comment on whether the differences in the exceptions between Common Rule and FDA-regulation would have any impact on stakeholders and whether there are possible approaches to avoid or minimize any potential negative effects of the differences, such as whether additional exceptions from the proposed single IRB review requirement should be included or whether providing guidance on the application of FDA's proposed exceptions might help avoid or minimize any differences in exceptions.

The FDA also requested comment on whether there are unique challenges to use of a single IRB review model for FDA-regulated cooperative research that could not be addressed by FDA's proposed exceptions. “For any challenges identified, we seek comment on whether additional exceptions should be included to address them,” the agency said.

“We do not believe it is practicable to rely on a broad exemption that would provide for FDA to make case-by-case determinations that use of single IRB review is not appropriate for the particular context as the only means for excepting FDA-regulated cooperative research – other than research for which more than single IRB review is required by law,” the FDA said.

“The agency also believes that situations in which use of a single IRB might not be appropriate and in which none of FDA's proposed exceptions apply would be rare. However, we seek comment on whether including an exception that provides for FDA to determine and document that single IRB review is not appropriate for the particular context, in addition to the exceptions FDA has proposed, could help address any such situations and any negative impacts of differences between FDA's proposed exceptions and exceptions available under the revised Common Rule,” the notice said.

The FDA also is requesting comment on the proposed exceptions and any other criteria that should be considered when assessing whether an exception to the use of single IRB review might be warranted. “We also encourage the public to provide examples of any additional types of FDA-regulated clinical investigations that they believe should qualify for such an exception,” the agency said.

The FDA also is proposing new regulatory text specifying that an institution participating in cooperative research that is not subject to the requirement for single IRB review may enter into a joint review arrangement, rely on the review of another IRB, or make similar arrangements for avoiding duplication of effort.

The agency also is proposing to require that research taking place at an institution in which IRB oversight is conducted by an IRB that is not operated by the institution, the institution, or where appropriate the IRB, documentation must be retained specifying the institution's reliance on the IRB for oversight of the research and the responsibilities that each entity will undertake to ensure compliance with the requirements of 21 C.F.R. Part 56 (e.g., in a written agreement between the institution and the IRB, by implementation of an institution-wide policy directive providing the allocation of responsibilities between the institution and an IRB that is not affiliated with the institution, or as set forth in a research protocol). “This proposed provision is consistent with the revised Common Rule's requirements at 45 C.F.R. §46.103(e) and 45 C.F.R. §46.115(a)(9). This proposed requirement is necessary for documenting compliance with Part 56 to provide a record for FDA's oversight and compliance purposes,” the agency said.

Other Revisions Proposed for IRB Rules

The FDA also proposed a new 21 C.F.R. 56.109(g), which would eliminate the requirement for an IRB to conduct continuing review of research, unless an IRB determines otherwise, 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, to harmonize with the revised 45 C.F.R. 46.109(f)(1)(iii).

“In these circumstances, FDA believes that requiring continuing review would generally not provide added protection to human subjects, and therefore, would not be necessary. When the only remaining research activities are limited to analysis of data or biospecimens that are part of the IRB-approved study, there is little or no risk to human subjects that would be addressed by requiring continuing review,” the agency said.

“Furthermore, after all subjects have enrolled and completed the protocol-specified interventions and interactions (including required follow-up study visits) to support the study's objectives, a protocol may include a long-term follow-up phase during which subjects continue to be monitored as they undergo clinical care for their medical condition or disease by their healthcare provider,” the notice said.

“During this continued follow-up phase, information regarding long-term clinical outcomes may be obtained through accessing clinical data generated during the course of clinical care. This proposed rule would eliminate the requirement for continuing IRB review for this follow-up portion of the study, unless the IRB determines otherwise.”

The agency noted that the revised Common Rule contains two other provisions identifying circumstances in which continuing review would not be necessary. “We are not proposing to adopt the revised Common Rule provision at 45 C.F.R. §46.109(f)(1)(i), which eliminates the requirement for an IRB to conduct continuing review of research that is eligible for expedited review in accordance with 45 C.F.R. §46.110 unless the IRB determines otherwise,” the FDA said.

“It is not practicable for FDA to adopt this provision because continuing review for minimal risk FDA-regulated clinical investigations would provide meaningful protections to human subjects participating in such investigations,” the agency said. “Continued IRB oversight of such studies would offer added human subject protection to those participating in such investigations by enabling the IRB to assess whether there are any additional risks that present more than minimal risk to participants and require discussion and/or action.”

“As we continue to consider how other provisions of the revised Common Rule could be applied to FDA-regulated research, including the revised Common Rule's exemptions, we may take additional steps to harmonize with such provisions at a later time,” the agency added.

The FDA also proposed adding a new 21 C.F.R. §56.109(c)(3) 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 agency noted the revised Common Rule has an exception to the requirement for documentation of informed consent at 45 C.F.R. §46.117(c)(1)(i) for situations in which the only record linking the subject and the research would be the informed consent form and the principal risk would be potential harm resulting from a breach of confidentiality.

“FDA's regulations historically have not included this same exception, and we are not proposing to add it in this rulemaking because we do not believe it is relevant to FDA-regulated research. We are, however, requesting comment on whether this provision is relevant to FDA-regulated research and any examples of situations when it would be useful,” the agency said.

The agency proposed amending 21 C.F.R. §56.107(a) to require that an IRB's membership reflects diversity of professional qualifications, and other factors including race, gender, and cultural backgrounds.

The FDA is also making revisions to clarify that IRB records may be maintained in electronic formats and that reference to federal, state and local laws or regulations, is intended to include tribal law.

The FDA also proposed requiring the IRB to maintain a record of the rationale for conducting continuing review, if the IRB determines that continuing review of research is necessary.

Submit electronic comments on the proposed rule by Nov. 28 in Docket No. FDA-2021-N-0286 via www.regulations.gov.