FDA recently published five sets of slides detailing inspection observation trends for IRBs, GLP laboratories, investigators, and sponsors/Contract Research Organizations for fiscal year 2022, which ran from October 1, 2021 until September 20, 2022. Unlike the inspection data dashboard, these metrics differentiate by inspectee, with one slide deck presenting information for each inspectee type and a fifth deck providing an overview. The metrics are surprisingly difficult to parse; we've spent a not insignificant part of our weekend musing over whether a particular color in a chart looks more like Pantone 1409759 TCX, Daffodil, or 12-0826 TCX, Golden Haze. See what you think!
Let's start with sponsor and CRO inspections. Per the overview slide deck, FDA's Bioresearch Monitoring Organization conducted 81 BIMO Sponsor, Monitor, and CRO inspections in FY2022. This number seems lower than the rough estimates we calculated based on FDA's dashboard data; however, many Contract Research Organizations also provide other services, so it is not always easy to categorize them without additional information.
66 out of 81 inspections, or 81.4%, were classified as No Action Indicated; 15, or 18.6%, were classified as Voluntary Action Indicated; and no inspections were classified as Official Action Indicated. These numbers and percentages are fairly consistent with FY2021, although going back in time we see the percentage of "VAI" inspections has trended downward from 27% in FY2017 to 15% in FY2022, while the percentage of OAI inspections has also trended down, from 5% to 0% over the same period. We've reformatted the data from the slide deck as a graph to provide more of a visual.
Only one sponsor or CRO Remote Regulatory Assessment was performed during this period.
In the 15 inspections classified as Voluntary Action Indicated, FDA has identified six "themes" in this slide deck:
- Inadequate case histories
- Inadequate monitoring
- Annual Report (IDE/IND) not submitted
- Failure to secure compliance
- Failure to submit an IND to FDA
- Inadequate IMP accountability
These trends are detailed in a graph that, while quite colorful, has no Y axis, so it is almost impossible to tell how many citations were issued within each theme. Take a look:
The columns for "inadequate case histories" and "inadequate monitoring" are 30% larger than the columns for the other themes. The inspection citations database indicates that 13 citations for inadequate IMP accountability were issued during FY2022; thus, we assume roughly 17 citations for the first two themes and 13 for the others. Note that the graph includes 13 different citations, each represented by a different color, but some of the colors are utilized in more than one "theme" (blue, light orange, and yellow). The dark orange color doesn't appear to have any corresponding citation number. Its closest match is the color corresponding to 21 CFR 812.2 (b), but this citation ("A clinical investigation that was determined to be a non-significant risk device study does not meet the abbreviated requirements for investigational device exemptions (IDEs)") appears to fit better with the "Annual Report (IDE/IND) not submitted" theme than with the "Failure to secure compliance" theme.
Let's start with the chart above. "Inadequate monitoring" and "failure to secure compliance from sites" are perennial inspection themes themes. Lack of safety or compliance monitoring, lack of adherence to the monitoring plan, continuation of ineligible subjects, lack of adherence with visit schedule, and use of unapproved informed consents gave rise to these citations.
"Failure to submit an IND to FDA" is also a fairly standard finding, typically generated when an academic researcher initiates a study of an unapproved product without applying for an IND.
"Inadequate case histories" appears to be an unusual citation for a sponsor inspection, but the slide deck gives some clarifying detail. Citations were due to lack of audit trails on electronic records; raw data inconsistent with submitted data; inability to verify subject eligibility; and inability to verify subject disposition, all of which relate back to data integrity.
"Inadequate IMP accountability" is the real outlier. Per the citations database, this issue was cited 13 times in 15 inspections classified as VAI, a considerable uptick in frequency since FY 2017, when it was cited 19 times in 40 inspections classified as VAI or OAI. In our experience as auditors, we see quite a few issues with IMP accountability, particularly missing records, numbers that don't add up, lack of identifiers on accountability records, and lack of trial-level accountability. Given the reduction in on-site monitoring visits post-pandemic, this metric does not surprise us at all.
To complicate matters, the summary slide deck presents a slightly different set of "Common Sponsor/CRO Inspectional Observations." One common observation in the overview deck that is not in the detailed deck is "Failure to submit current list of all participating investigators to FDA at six-month interval after FDA approval of the study" (812.150 (b) (4), a device regulation).
Our takeaway? Data integrity and drug accountability are areas to watch. Don't conduct research without an IND. And "failure to secure compliance" looks like a lovely color for an accent wall.
