Exceptions for Continuing Review in the NPRM

Institution Bulletin vol. 5, issue 4

The September 2015 notice of proposed rulemaking (NPRM),[1] published some five years after the advanced notice,[2] balances the guiding ethical principles with a clear focus on efficiency in human subject research. In doing so, the NPRM creates additional regulatory flexibility by reducing the need for continuing review when it does not meaningfully enhance protection of participants.[3]

Recognizing the heavy workload at many IRBs, the NPRM re-prioritizes and more efficiently allocates resources to activities most protective of participants. Estimates within the NPRM suggest that 90 percent of continuing reviews could be eliminated if the reforms were enacted. Since continuing review comprises an estimated 52 percent of all protocol reviews,[4] the cost savings is expected to exceed $100 million over a ten-year period. Furthermore, according to the proposal, this reform could be accomplished without a detrimental effect on the rights and welfare of participants.[5] Such a dramatic decline in continuing review is accomplished by consolidating review around greater than minimal risk research, where the majority of scrutiny should be focused.

The basic premise of continuing review remains essentially the same: “An IRB shall conduct continuing review of research covered by this policy at intervals appropriate to the degree of risk, but not less than once per year…”[6] However, the NPRM adds a new paragraph (f)[7] to the existing regulation. This new text contains three specific exceptions that—if all goes to plan—will swallow the general rule.

Exception 1
Continuing review would not be required for the majority of minimal risk studies. Specifically, minimal risk studies that qualify for expedited review[8] would not be subject to continuing review unless the reviewer provides a rationale at the time of initial review as to why continuing review should nonetheless occur.[9]

Exception 2
Continuing review would not be required after all research interventions have been completed and the study has reached the stage where it only involves one or both of the following: (A) analyzing data and/or (B) accessing follow-up clinical data from procedures that participants would undergo as part of standard care.[10]

The NPRM clarifies that analysis of identifiable private information still will not require continuing review and that routine care includes, for example, periodic CT scans to monitor cancer recurrence or progression.[11]

Exception 3
Under new limited IRB review provisions,[12] continuing review would not be required for certain secondary research using information and biospecimens.[13]

These exceptions are not without controversy. Based on comments in the 2010 advanced notice of proposed rulemaking (ANPRM), some respondents feel the exceptions reduce oversight responsibility and question whether the scales have been appropriately weighted toward participant protection. For example, comments in the ANPRM raised concerns about reducing IRB-investigator communication and enabling rogue investigators.[14]

Yet the NPRM contains provisions that should allay concerns about additional liability stemming from increased noncompliance among research. Institutions will have significant flexibility to operate within the new regulatory paradigm without imposing onerous requirements. Administratively, in lieu of Board review, an IRB must still receive annual confirmation that such research is ongoing and that no changes have been made that would require the IRB to conduct continuing review.[15]

The NRPM explains that the confirmation process could be as simple as an automated electronic communication in which the investigator responds “Yes” to indicate that the study is ongoing without change.[16] Alternatively, an IRB could devise procedures to gauge specific progress or adherence to GCPs and to alert for potential problems. In either case, existing infrastructure to send reminders for continuing review could be re-purposed for this confirmation process.

Furthermore, continuing review may yet be conducted, even if falling within one of the three new exceptions, if the IRB records the rationale for its determination that such review occur. The NPRM requires that the institution or IRB prepare and maintain adequate documentation of its continuing review activities.[17] Therefore, local procedures will stipulate the extent of documentation and, likely, the circumstances under which continuing review may be an institutional requirement above and beyond the regulations. Notably, in response to overwhelming opposition, the NPRM does not require submission of reports detailing when an IRB elects to conduct continuing review.[18] As a result, NPRM estimates suggest that 10 percent of studies will require new recordkeeping.[19]

Importantly, the NPRM does not alter investigators’ reporting obligations related to unanticipated problems or changes to the protocol.[20] The Board must still review these as they arise. Presumably, any such instances would need to be reported to the IRB until the investigator administratively closes the study.

Ongoing research initiated prior to the effective date of the final rule may—but need not—comply with the continuing review requirements, and the continuing review requirements could be voluntarily implemented as soon as 90 days from the publication of the final rule.[21] Ultimately, by limiting continuing review, the NPRM focuses on the information most critical to the protection of research participants and eases the administrative burden on all involved in human subject research.


 

[1] Federal Policy for the Protection of Human Subjects, 80 Fed. Reg. 53,933 – 54,061 (proposed Sept. 8, 2015) (available at http://www.gpo.gov/fdsys/pkg/FR-2015-09-08/pdf/2015-21756.pdf) [hereinafter Federal Policy].

[2] Human Subject Research Protections: Enhancing Protection for Research Subjects and Reducing Burden, Delay, and Ambiguity, 76 Fed. Reg. 44,512 – 44,531 (proposed July 26, 2011) (available at http://www.gpo.gov/fdsys/pkg/FR-2011-07-26/pdf/2011-18792.pdf) [hereinafter Human Subject Research Protections].

[3] It is important to note from the outset that this proposal will not necessarily be consistent with FDA’s regulations. Therefore, FDA-regulated trials may require continuing review (CR) to a greater extent. Federal Policy, supra note 1, at 53,981. While this possible divergence certainly has the potential to increase institutional and IRB burden, the FDA intends to modify its regulations in light of the NPRM. Id. For the FDA’s most recent thinking on CR, see U.S. Food & Drug Admin., Guidance For IRBs, Clinical Investigators, and Sponsors: IRB Continuing Review after Clinical Investigation Approval (2012), available at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294558.pdf (last accessed Nov. 4, 2015).

[4] Federal Policy, supra note 1, at 53,998. Continuing review requires significantly less time for all involved, however, as compared to initial review. Id.

[5] Id. at 54,014, 15.

[6] Compare 45 CFR 46.109(e) (2015), with Federal Policy, supra note 1, at 54,051 (to be codified at __ C.F.R. § __.109(e) (substituting “covered by this policy” with “requiring review by the convened IRB”).

[7] Federal Policy, supra note 1, at 54,051 (to be codified at __ C.F.R. § __.109(f)).

[8] Id. (to be codified at __ C.F.R. § __.109(f)(1)(i)).

[9] Id. at 53,985 (to be codified at __ C.F.R. § __.115(a)(8)).

[10] Id. at 54,051 (to be codified at __ C.F.R. § __.109(f)(1)(ii)).

[11] Id.

[12] Id. at 53,985 (to be codified at __ C.F.R. § __.111(a)(9)).

[13] Id. at 54,051 (to be codified at __ C.F.R. § __.109(f)(1)(iii)).

[14] Additionally, the NPRM addresses concern over an inability to ascertain when a study closes, without CR. Regulations do not require notice of closure. Citing OHRP guidance, the NPRM indicates that an IRB is free to require closure reports. Id. at 54,044.

[15] Id. at 53,985 (to be codified at __ C.F.R. § __.109(f)(2)). This process does raise the question as to whether an IRB would have the authority to require confirmation more frequently than “on an annual basis”, consonant with the authority to impose shorter than yearly CR intervals.

[16] Id. 53,985.

[17] Id. at 54,052 (to be codified at __ C.F.R. § __.115(a)(3)). It is not entirely clear as to whether this record or documentation for CR can be passive (for example, generalized procedures that identify prescriptive classes of research or investigators that will require CR), whether a formal determination must be made for each protocol at the time of initial review, or whether a combined approach would be most acceptable.

[18] Human Subject Research Protections, supra note 2, at 44,518. Comments to the ANPRM persuasively argued against the requirement that periodic reports be submitted to OHRP for informational purposes, as it would deter CR and significantly undermine the efficiency gains that are the very purpose for the rulemaking. See Federal Policy, supra note 1, at 54,044.

[19] Id. at 54,014.

[20] Id. at 53,985.

[21] Id. at 53,993.

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