Improving and Preventing Lapse in Institutional Review Board Continuing Review Approval
Protection of human research subjects is an ethical mandate for all contemporary clinical trials. Continuing review of on-going research is one way by which institutional review boards (IRBs) ensure that human subjects participating in research are adequately protected. It is through continuing reviews that IRBs determine whether research is conducted according to the approved protocols, adverse events are properly reported, and risks to subjects remain reasonable relative to anticipated benefits from the research [1-3].
Despite its importance, scant research focuses on IRB continuing reviews. Little is known about the prevalence of lapse in IRB continuing reviews, factors that may contribute to it, and measures that IRBs may take to prevent or improve lapse in IRB continuing reviews.
We conducted a review of the literature on IRB continuing reviews. The literature search included the United States National Library of Medicine PubMed database and a web search for federal regulations and guidance on IRB continuing reviews. The data were analyzed for the requirements of IRB continuing reviews, the frequency and factors affecting lapse in IRB continuing reviews, and measures that had been shown to improve or prevent a lapse in IRB continuing reviews.
IRB continuing review requirements
The U.S. Federal Policy for the Protection of Human Subjects, also known as the Common Rule, requires that IRBs conduct continuing review of human research at intervals appropriate to the degree of risk, but not less than once per year. Institutional review boards must maintain and follow written procedures for conducting continuing reviews of research projects. In order to re-approve research protocols at continuing reviews, IRBs must ensure that the research has satisfied all eight Common Rule criteria: minimization of risks to human subjects, reasonable risk to benefit ratio, equitable selection of subjects, requirement of informed consent, documentation of informed consent, monitoring of subject safety, maintaining subject privacy and confidentiality of data, and additional safeguards for vulnerable subjects when appropriate [2,3].
In 1995, Nightingale reported that one of the most common deficiencies identified by the Food and Drug Administration (FDA) was an inadequate or late review of active research protocols . A 1996 Government Accountability Office report also noted that IRB continuing reviews were typically either superficial or not done at all . It was speculated that the underlying cause of this deficiency was that many IRBs were overworked and under-supported by their institutions. A more recent review of 52 warning letters issued to IRBs by FDA from 1997 through 2003 revealed that 36 warning letters (69%) cited IRBs for failure to provide adequate continuing reviews of research protocols . The problem with IRB continuing reviews did not appear to be unique to the United States. In 2008, Norton and Wilson reported that 13% of Canadian research ethics boards did not conduct continuing ethics review of approved studies, even though the Canadian Tri-Council Policy Statement on Ethical Conduct for Research Involving Humans required that at a minimum the research ethics boards should review an annual report submitted by the researcher . Thus, inadequate and/or lapse in IRB continuing reviews appear to be a major problem in human research protections. However, none of these studies provided actual rates of a lapse in IRB continuing reviews.
Table 1. Lapse in institutional review board continuing review approval.
Lapse in IRB continuing review approval
Lapse in IRB continuing review approval occurs when investigators fail to provide required continuing review application to the IRB or fail to submit applications in time for the IRB to review and reapprove prior to the IRB approval expiration date, and/or IRBs fail to conduct continuing reviews and reapproved the research by the expiration date of IRB approval. Federal regulations do not allow for any grace period extending the conduct of research beyond the expiration date of IRB approval[2,3].
Thus, when lapse in IRB continuing review approval occurs, all research activities involving human subjects must stop, unless the IRB determines that it is in the best interests of subjects who are already enrolled in the study, to continue participating in the research. Under this circumstance, new subjects may not be enrolled, and continuing participation of those already enrolled may be appropriate only when the research interventions hold out the prospect of direct benefit to the subjects or when withholding those interventions poses increased risk to them [2,3] .
Since 2010, the Department of Veterans Affairs (VA) Health Care System has collected and published quality indicator data, including IRB continuing review performance metric data,from its 108 research facilities as part of its human research protection quality assurance program [1,8-10]. A review of the literature revealed that no other institutions have published any IRB continuing review performance metric data.
Of the 25 VA human research protection program performance metrics collected annually from 2010-2013, lapse in IRB continuing review approval had the highest noncompliant rate [1,9].
Table 2. Lapse in continuing reviews according to types of institutional review board useda.
As shown in Table 1, lapse rates of IRB continuing reviews remained relatively constant at 6% to 7% from 2010 through 2013. However, in less than 3% of lapsed protocols, investigators continued research activities, excluding those activities that were deemed by the IRBs to be in the best interest of already-enrolled subjects, during the lapses [1,9].
Comparing facilities using own VA IRBs, other VA IRBs, or affiliated university IRBs, there were no statistically significant difference in IRB continuing review lapse rates (Table 2) [1,9]. Likewise, comparing facilities with different sizes of human research programs, there were no statistically significant difference in IRB continuing review lapse rates (Table 3) [1,9]. Thus, neither the types of IRBs used, nor the sizes of human research programs, had any effects on the lapse rate of IRB continuing reviews.
Table 3. Lapse in institutional review board continuing reviews according to program sizesa.
aResults were expressed as mean (±SD) of data from 2010 to 2013.bp values: 0.0221 (small vs. medium); 0.1245 (small vs. large); and 0.2973 (medium vs. large). [Student’s t test with Bonnferoni correction for multiple comparisons was used to determine the level of significance. After Bonferroni correction for multiple comparison (n = 3), in order to be considered statistically significant, p value needs to be < 0.017)].
Analysis of facilities with various lapse rates revealed that approximately 60% of facilities had no lapse in IRB continuing reviews, while approximately 20% of facilities had lapse rates of >10% each year (Table 4). In addition, a number of facilities appeared to be repeat offenders. Ten facilities (9.2%) had lapse rates of >10% in 3 or 4 years from 2010 through 2013, suggesting a system problem in these facilities’ IRB continuing review approval processes [1,9] .
Table 4. Number of facilities with various institutional review board continuing review lapse ratesa.
aResults were expressed as mean (±SD) of data from 2010 to 2013.
Improving and preventing lapse in IRB continuing reviews
To avoid lapse in IRB continuing reviews, the Office for Human Research Protections of the Department of Health and Human Services recommends that IRBs and investigators plan ahead to ensure that continuing review and re-approval of research occurs prior to the end of the approval period specified by the IRB; IRB’s written procedures should provide for sufficient advance notice to the investigator to ensure that the requirements for continuing review are met by the approval expiration date; and IRBs should develop administrative procedures, such as computerized tracking systems, to minimize any unintended expiration of IRB approval  .
Ten VA research facilities with IRB continuing review lapse rates that were higher than the VA national average for 3 consecutive years from 2011 to 2013, developed and implemented remedial action plans to improve their IRB continuing review lapse rates. Eight of these 10 facilities showed markedly improved lapse rates in IRB continuing reviews after implementing remedial action plans. The mean lapse rate of these 8 facilities was 28.5% (± 13.9%, SD) in 2013 prior to the implementation of remedial action plans, while it was 6.7% (± 8.6%) in 2014 after the implementation (p = 0.0017). The other two facilities failed to fully implement their remedial action plans and did not show any improvement .
Remedial measures that these 8 facilities found to be most effective in improving lapse rates of their IRB continuing reviews, included: tracking expiration dates of IRB approval; notifying investigators at least 60 days prior to approval expiration; investigator training and education; follow-up with investigators to ensure that continuing review application was submitted in time for IRB review; and stopping all research activities when lapse occurs  .
Considerable efforts have been made to improve the protection of research subjects since early 2000 . However, despite