On September 28, the US Food and Drug Administration (FDA) released two Notices of Proposed Rulemaking (NPRMs) to harmonize the FDA regulations on the protection of human subjects and institutional review boards with the 2018 Common Rule.
The proposed rules, together, harmonize “to the extent practicable and consistent with other statutory provisions,” the single IRB requirement for cooperative research, informed consent requirements, continuing review provisions, associated recordkeeping provisions, and some definitions, as well as make some additional formatting and editorial changes for clarity.
In my last post, I provided some background about harmonization efforts and summarized the NPRM dealing specifically with single IRB review for cooperative research. In this post, I summarize the major provisions of the second NPRM, which is focused primarily on harmonizing language, definitions, and informed consent requirements in 21 CFR 50—Protection of Human Subjects, and on harmonizing provisions around continuing review, IRB review generally, and IRB membership, in 21 CFR 56—Institutional Review Boards.
21 CFR 50—Protection of Human Subjects
Informed Consent - FDA harmonizes with Common Rule general requirements
FDA is proposing to adopt wholesale the general requirements for informed consent at 45 CFR 46.116 (a) (1) through (6), including the key information requirement and the requirement that information be organized and presented in a way that facilitates the subject’s or their legally authorized representative (LAR)’s comprehension and decision about whether or not to participate in research (these will appear at 21 CFR 50.20).
FDA proposes the addition of a new basic element on biospecimens
As the revised Common Rule did, FDA is proposing to add a new basic element of informed consent about the potential future use of biospecimens or information for research; however, FDA is not proposing to adopt the Common Rule language for this element. The Common Rule requires that informed consent include one of the two following statements for research that involves the collection of identifiable private information or identifiable biospecimens—either that identifiers might be removed and information/biospecimens could be used for future research without additional informed consent—or, that the information and biospecimens will not be used for future research, even if identifiers are removed.
Given FDA’s mandate, from the Cures Act to accelerate the discovery, development, and delivery of new medical products, FDA notes that it has concerns about the practicability of limiting this element of consent to the two situations addressed by the Common Rule. FDA prefers to allow flexibility regarding what an investigator tells a potential subject or LAR about possible future uses of information and biospecimens. To that end, the proposed FDA regulations add the following new basic element of informed consent: “A description of how information or biospecimens may be used for future research or distributed to another investigator for future research.” (21 CFR 50.25[a]).
FDA looks to add three additional new elements of informed consent
FDA proposes to add the following three new additional elements of informed consent, harmonized with the Common Rule:
- A statement that the subject’s biospecimens (even if identifiers are removed) may be used for commercial profit (21 CFR 50.25[b])
- A statement on whether clinically relevant research results, including individual research results, will be disclosed to subjects, and under what circumstances (21 CFR 50.25[b][a])
- A statement about whether the research will or might include whole genome sequencing (21 CFR 50.25[b])
One area regarding informed consent where the FDA regulations are not adopting revised Common Rule language is around the provision at 45 CFR 46.116(g) allowing IRBs to approve research in which investigators obtain information or biospecimens without seeking informed consent for the purposes of screening, recruiting, or determining study eligibility, if certain conditions are met. FDA explains that adopting this provision would be at odds with its longstanding view that some specific preparatory activities to clinical trials do not fit its definition of clinical investigation, and so would not require IRB review or informed consent in any case.
Rule also proposes to harmonize definitions
The FDA’s rule also proposes to harmonize key definitions with the Common Rule, including:
- Revising the definition of Legally Authorized Representative (LAR) to match that in the Common Rule
- Adding definitions for the following terms harmonized with those in the Common Rule:
- Written or in writing, which would include both paper and electronic format
- Identifiable information
- Identifiable private information
- Identifiable biospecimens
FDA adds the word “sponsor” to the last two definitions to clarify that private information and biospecimens are considered identifiable if the investigator or sponsor can readily ascertain the subject’s identity.
Finally, the FDA makes some minor editorial changes, grammatical corrections, and removes obsolete, language throughout 21 CFR 50.
21 CFR 56—Institutional Review Boards
The most significant area of harmonization in the FDA regulations at 21 CFR 56 is around continuing review.
Specifically, FDA is proposing a new provision, mirroring the Common Rule, that would eliminate the requirement for an IRB to conduct continuing review of research that has progressed to the point that it involves only data analysis and/or accessing follow-up clinical data from procedures that subjects would undergo as part of clinical care, unless the IRB determines otherwise (21 CFR 56.109[g]). FDA is correspondingly proposing to add language at 21 CFR 56.115[a] that would require IRBs to maintain a record of the rationale for conducting continuing review when it is not otherwise required, again, harmonizing with the provisions in the Common Rule.
However, FDA is not harmonizing with two other Common Rule conditions under which continuing review may not be necessary: (1) for research that is eligible for expedited review unless an IRB determines otherwise and (2) for research that has been reviewed in accordance with the limited IRB review process. Regarding the former, FDA notes that OHRP has clarified that, until the 1998 HHS Expedited Review List is updated, for research to qualify for expedited review under the revised Common Rule, the IRB must also determine that the specific circumstances of the proposed research involve no more than minimal risk. FDA notes that it is not “practicable” for it to adopt this provision, because continuing IRB review for minimal risk FDA-regulated clinical investigations would still provide meaningful protections to human subjects, given that the risks to subjects receiving FDA-regulated products may change over the course of a study.
Regarding the latter, FDA has decided not to adopt the revised Common Rule’s limited IRB review provisions at this time, though, as I noted in my last post, the Agency hints that it may harmonize in this area at a later date.
The FDA is not proposing any changes to the expedited review provisions at this time. This is partly because while there were new provisions regarding expedited review in the revised Common Rule, they are yet to go into effect. As noted above, OHRP has clarified that the old provisions around expedited review remain in effect until the 1998 HHS Expeditated Review List is updated. FDA notes that the categories of research eligible for expedited review referenced in the FDA regulations at 21 CFR 56.110(a) are identical to the categories in the 1998 HHS Expedited Review List—in other words, the current FDA regulations are harmonized with the Common Rule as it is currently implemented.
It's also worth noting that FDA seems to disagree that all the categories of research described in the expedited review list involve only minimal risk. For example, Category 1 on the list includes clinical studies of drugs and medical devices that do not require an IND or IDE application. But “FDA does not presume" that all such clinical studies “present no more than minimal risk to subjects.” Therefore, the Agency says it is keeping the requirement at 21 CFR 56.110(b) that for research to qualify for expedited review, it must appear on the list and the reviewer must determine the research involves no more than minimal risk.
All of that said, FDA notes that it intends to participate in the process, required by the revised Common Rule, to evaluate the HHS expedited review list at least every eight years, and amend it as appropriate. FDA would update its own expedited review list during that process and consider whether changes to its regulations are needed.
Other provisions and changes in 21 CFR 56 include:
- Clarifying that references to federal, state, or local laws intend to include tribal law aligned with the Common Rule.
- Harmonizing language on IRB membership at 21 CFR 56.07(a) with the language in the revised Common Rule at 45 CFR 46.107(a).
- Adding a new exception to the requirement to document informed consent (at 21 CFR 56.109]c]), harmonized with the Common Rule, which allows the IRB to waive documentation of informed consent for minimal risk studies if the subject or LAR are members of a distinct cultural group or community in which signing forms is not the norm, and there is no appropriate alternative for documenting consent.
- Updating language, consistent with Common Rule, describing categories of people who are vulnerable to coercion and undue influence, in the criteria for IRB approval of research at 21 CFR 56.111.
- Minor editorial, grammatical, and definitional changes, as well as moving some language to new sections.
Revisions to 21 CFR 812— Investigational Device Exemptions
Finally, this NPRM proposes some revisions to 21 CFR 812—Investigational Device Exemptions, revising requirements for progress reports from investigators to sponsors and from sponsors to reviewing IRBs—so they are consistent with the proposed continuing review provisions.
According to the notice, the new rules will go into effect 180 days after the final rule is published in the Federal Register.
Make Your Voice Heard
Deadline for comments is December 28, 2002
This is the regulated community’s chance to weigh in on FDA’s new proposed rules for IRBs and protection of human subjects. For general information on how to submit a formal comment go to primr.org.
The deadline for submitting comments is December 28, 2022. Submit your comments HERE.
PRIM&R will be submitting our own comments on both of these proposed rules, and if we can, we will share those comments here on the blog before the due date so you can reference them. In the meantime, please share any thoughts you have about these guidelines, and how you foresee them affecting your work.
For a closer look at the proposed rules, the PRIM&R Annual Conference (PRIMR22) will hold a virtual workshop highlighting the new FDA NPRMs: Applying the FDA Framework in Conducting IRB Review.