On September 28, the US Food and Drug Administration (FDA) released two Notices of Proposed Rulemaking (NPRMs) aimed at harmonizing the FDA regulations for 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 requirements, and some definitions, as well as making some additional formatting and editorial changes for clarity.  

The current proposed rules do not address provisions for limited IRB review, broad consent, posting of consent forms, exempt research, or public health surveillance activities, all of which are “potentially relevant” to FDA-regulated research. FDA hints that it plans to take additional steps to harmonize its regulations in these areas with the Common Rule, so perhaps we can expect additional proposed rules in the months to come. The regulated community now has about two months—until November 28, 2022—to share feedback on these two proposed rules. 

In this post, I will provide some background on harmonization efforts, and then summarize the substance of the  proposed rule concerning single IRB (sIRB) review for cooperative research. In the next post, I will outline the main provisions of the proposed rule dealing with human subjects protections and IRBs.

Background on Harmonization Efforts between the Common Rule and FDA regulations
The FDA is not a signatory to the Common Rule, due to differences between FDA’s mission and statutory authority and that of HHS and other Common Rule agencies. The Common Rule, promulgated by the Office for Human Research Protections (OHRP) within HHS, regulates any human subjects research conducted or supported by a federal department or agency that is a signatory to the Rule. The FDA regulations, on the other hand, apply to clinical investigations that support applications for research or marketing permits for products regulated by the FDA, including drugs, medical devices, and biological products for human use, regardless of funding source. Given that some FDA-regulated research is also federally funded, some IRBs must review research under both sets of rules.  

Prior to the revisions to the Common Rule in 2017, the FDA regulations were largely consistent with the Common Rule; differences between them had to do, again, with differences in agency mission and statutory authority. The recent revisions to the Common Rule resulted in significantly larger differences between the two sets of rules, potentially increasing confusion and administrative burden for institutions and IRBs. Harmonization was mandated by section 3023 of the 21st C. Century Cures Act, passed at the end of 2016 (when the revisions to the Common Rule were still in process, but expected), and while FDA has published guidance over the last few years to clarify how complying with some aspects of the new Rule is consistent with FDA regulations, the community has been eagerly awaiting rulemaking in this area. 

New FDA Requirement for sIRB Review for Cooperative Research 
One NPRM released last week deals narrowly with the provisions around cooperative research at 21 CR 56.114, adopting the revised Common Rule’s requirement for single IRB review for cooperative research (and associated recordkeeping requirements).

While the current FDA regulations “encourage” sIRB review for cooperative research, the new FDA rule would “require any institution located in the United States participating in FDA-regulated cooperative research to reply on review and approval by a single [IRB] for that portion of the research conducted in the United States, with some exceptions.” The list of exceptions, however, differs from the list in the Common Rule.  

Exceptions to the sIRB Requirements 
The Common Rule includes two exceptions to the sIRB review requirement: (1) when more than sIRB review is required by law (including tribal law), and (2) when the federal department or agency conducting or supporting the research decides that use of an sIRB is not appropriate (45 CFR 46.114[b]).

The FDA proposes to adopt the first exception, but not the second, given that most of the research that FDA regulates is not supported or conducted by any federal department or agency—though it asks for public comment about whether it should harmonize this exception as well. (This is a good example of why full harmonization is not possible or desirable, given the differences in agency mission and statutory authority).  Instead, FDA proposes several additional, specific exceptions to the sIRB requirement (outlined below)

FDA Justification for sIRB Exceptions
In the preamble, the FDA explains its justification for considering additional exceptions. The agency acknowledges that there may be significant initial burdens associated with the move to sIRB review, such as establishing reliance agreements. And while it agrees with the Common Rule agencies that for much FDA-regulated research, sIRB review will on balance and in the long run decrease administrative burdens and inefficiencies that don’t add to subject protections, FDA says it does “not believe that it is clear that the potential benefits of single IRB review outweigh the potential associated burdens in every circumstance.” The exceptions it is proposing account for situations where, according to FDA, the burdens of sIRB review are not likely to be outweighed by its benefits.

The proposed exceptions are:  

• Cooperative research involving a “highly specialized FDA-regulated medical product” for which localized expertise may be required. 
• Cooperative research on drugs that are exempt from the requirements for an IND application under 21 CFR 312.2.(b) (because “increased efficiencies” associated with sIRB review in these circumstances “would not provide the benefit of bringing new drugs or new uses of drugs to patients sooner”) 
• Cooperative research on medical devices that meet the abbreviated requirements (under 21 CFR 812.2(b) or that meet the requirement for exempted investigations under 21 CFR 812.2(c) (because “the initial administrative burden of establishing cooperative review agreements may not be offset by the anticipated benefits of sIRB review efficiencies”) 

Possible Additional Exceptions
The FDA goes on to requests public comment regarding whether additional exceptions—including for categories of cooperative research identified by SACHRP—are warranted, for instance: 

• When use of a sIRB is unable to meet the needs of specific populations; 
• When cooperative research involves a small number of investigational sites;
• Any other challenges to use of sIRB review for FDA-regulated cooperative research that is not addressed by FDA’s proposed exceptions.

The proposed rule makes clear that even cooperative research that would qualify for an exception from the sIRB requirement may still use single IRB review—that is, FDA would permit the use of a sIRB in these circumstances. This helps to address the concern that a cooperative research project that is both FDA-regulated and subject to the Common Rule might qualify for an FDA exception but be required to use sIRB review under the Common Rule.  

Though FDA is presumably open to comment on any aspect of this NPRM, its specific requests for public comment focus exclusively on the list of exceptions: whether it is appropriate and adequate, and whether there are examples of other types of cooperative research that should be considered.  

FDA proposes the effective date for the proposed rule requiring sIRB review of cooperative research be one year after the final rule is published in the Federal Register.  

Make Your Voice Heard 
This is the regulated community’s chance to weigh in on FDA’s new proposed rules regarding sIRB and cooperative research. For general information on how to submit a formal comment go to primr.org.

Submit your comments here  https://www.regulations.gov/document/FDA-2019-N-2175-0001. The deadline for submitting comments is November 28, 2022. 

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, below.  

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