sensitivity analysis

FDA Clinical Inspection Summary: Imfinzi (durvalumab) submitted by Astra Zeneca

FDA did not post any warning letters to Sponsors/Monitors/CROs, IRBs or Clinical Investigators this week. From the archives, here is the Clinical Inspection Summary for Imfinzi (durvalumab) submitted by Astra Zeneca. Three sites (out of the 79 that participated in the trial) plus the sponsor were inspected. Site inspections ranged from four days to five weeks. One site received a FDA Form 483.

Dr. O'Donnell was cited for the following (Note: He was the third PI at the site, but was cited for all regulatory violations on the study):

  • Reporting seven Serious Adverse Events outside of protocol required timelines. FDA notes that four of these events were not included in the BLA data listings because the cut-off date was missed.
  • Listing that three subjects had withdrawn consent when they had not. FDA notes that this meant adverse events were not reported as required after the treatment period.
  • Forty-two (42) adverse events were not reported to the sponsor as required for four subjects. FDA required that a sensitivity analysis be performed on the study datasets with the data from this site removed, in order to determine if the under-reporting of adverse events from this site affected study outcomes. 

FDA Clinical Inspection Summary: Erelzi (etanercept-szzs) submitted by Sandoz

FDA did not post any warning letters to Sponsors/Monitors/CROs, IRBs or Clinical Investigators this week. From the archives, here is the clinical inspection summary for Erelzi (etanercept-szzs) submitted by Sandoz. Three sites plus the sponsor were inspected. Sites were selected on the basis of high enrollment and protocol deviations. All of the site inspections and the sponsor inspection lasted four days. Once site received a FDA Form 483.

Dr. Kingo was cited for failing to follow the investigational plan, specifically:

  • Failing to enter the type of prior therapy into the electronic Case Report Form (CRF). 

In reviewing the inspection summary, FDA reports that due to all of the inspections, they were unable to confirm the reliability or reported prior therapy and therefore could not confirm that the protocol required stratification at randomization was accurate. FDA further states that a number of reasons led to this problem: lack of understanding of clinical staff including monitors of the definition and timelines of prior therapy, unclear protocol instructions and the delayed identification of the issue by the sponsor.

The sponsor had to amend the Biologics License Application (BLA) to further describe the issue, which resulted when the Sponsor's contracted data management vendor incorrectly told sites to remove evidence of prior therapy administered more than six months before study start. FDA also notes that the sponsor lacked an adequate electronic CRF to appropriate capture prior therapy. The sponsor was also required to conduct a sensitivity analysis of the impact of the stratification errors that resulted from the impact of the issues with the data surrounding prior therapy.