The data integrity issues most likely to lead to a delay in FDA marketing approval for new drugs include poor quality control for data entry, systemic errors at clinical study sites — such as enrolling ineligible patients — and database changes made after an initial database lock and study unblinding.
These are some of the key takeaways from a deep dive into the FDA’s own data on clinical trial inspections, said Beverly Lorell, senior medical and policy advisor for law firm King and Spalding’s FDA and Life Sciences Practice Group.
Lorell points to two important documents — the first is the FDA’s annually updated Bioresearch Monitoring (BIMO) Program Metrics, which provides details about each year’s inspections of sponsors, investigators and independent review boards; the second is a one-time study conducted by officials in the FDA’s Office of Scientific Investigations (OSI), which delved into a single year of agency actions around those BIMO inspections.
That study — Assessing Clinical Trial Quality: An Analysis of CDER’s Experience — found that there was a high degree of correlation between data integrity issues identified through inspections and FDA decisions to delay or even refuse marketing approval.
When CDER’s Office of Scientific Investigation receives data from a clinical study along with the findings from a BIMO inspection, it reviews the data and the inspection results and makes a formal recommendation to the Office of Drug Evaluation on two points:
- Whether the data from an individual site or sites is reliable and can be counted on in the review division’s analysis; and
- Whether the data from the clinical trial as a whole can reliably support an evaluation for the indication the sponsor is seeking.
The one-year study of CDER activity found that roughly one in every 20 marketing applications were delayed due to inspections that cast doubt on the validity of their clinical data.
“So these are very, very major issues,” Lorell said during an FDAnews webinar. She advises sponsors to think of data integrity not as some stand-alone issue of good bookkeeping, but rather as an integral part of data quality. “The quality of conduct of an FDA-regulated clinical investigation is inextricably intertwined with data integrity.”
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