Imaging

FDA Clinical Inspection Summary: Verzenio (abemaciclib) submitted by Eli Lilly

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 Verzenio (abemaciclib) submitted by Eli Lilly. Six sites were selected for inspection, based on high site specific efficacy results, participation in numerous other trials, low numbers of protocol deviations, low numbers of reported Serious Adverse Events (SAEs) and low numbers of deaths on study. Inspections ranged from three days to three weeks. Two sites received FDA form 483s.

Dr. Dickler was cited for:

  • Failing to report adverse events to the sponsor, specifically five adverse events from three patients.
  • Failing to prepare and maintain adequate and accurate case histories.
    • Failing to report concomitant medications for four subjects. FDA notes that the monitor had informed the site at the start of the trial that recording this information was unnecessary. 
    • One adverse event did not have a toxicity grading.
    • The source for two concomitant medications was missing.

Dr. Salinas was cited for:

  • Failing to prepare and maintain adequate and accurate case histories.
    • FDA notes numerous discrepancies and only provides a few examples (three and a half pages) in the Clinical Inspection Summary.
    • For example, the radiology scan indicated a tumor was 10.6 mm, but the data listings indicated the tumor measured 100.6 and the source worksheet indicated a measurement of 106 mm.
    • Other examples include source worksheets indicated radiology scans were missed, but values for these scans were in the data listings.
    • Lesions had sizes of 4.9 mm in the data listings, but source worksheets indicated that they were too small to measure and data entry conventions stated that lesions too small to measure should have a value of 5.0 mm assigned.
    • Data listings indicated stable disease, the radiology report indicated progressive disease and the source worksheet had "None" entered for tumor response.
    • FDA notes that a sensitivity analysis should be performed, as the above listed errors impacted the primary endpoint for three patients at the site.

 

FDA Clinical Inspection Summary: Alunbrig (brigantinib) submitted by Ariad

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 Alunbrig (brigantinib) submitted by Ariad. Four sites, plus the Sponsor and Contract Research Organization (CRO) responsible for the independent reads of the trial images were inspected. Site inspections ranged over 4 to 9 days, the Sponsor inspection took place over 4 days. One site and the CRO were issued FDA Form 483s.  

Dr. Kim was cited for:

  • Failing to follow the delegation of authority log. Specifically, the study coordinator assessed adverse events
  • Failing to document hand and arm pain as adverse events in one subject
  • Failing to permit FDA to copy reports. Specifically, the audit trail of the electronic medical record could not be printed

The unnamed CRO was cited for using a computer system prior to validation, specifically:

  • Implementing the software (Mint lesion) at a time when the vendor had disclosed that it was not 21 CFR 11 compliant
  • Validating the software without confirming that it complied with charter requirements for lesion measurement. (Note: images for 126 subjects were required to be reread due to errors by the software.)
  • The CRO did not comply with charter requirements for variability testing
  • Inadequate audit trails that did not capture information required by the charter for reasons items were reread.
  • Quality assurance checks for incoming images from clinical sites were not conducted in the timeframes required by the charter

FDA notes that due to the issues noted at the CRO in the inspection, the validity of the data from the CRO (the trial's primary endpoint) could not be verified

Clinical Inspection Summary: Lartruvo (olaratumab) submitted by Eli Lilly and Company

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 Lartruvo (olatumab) submitted by Eli Lilly and Company. Two sites plus the sponsor and the CRO managing the independent review of radiology images for the study were inspected. Site inspections ranged over seven to eleven days and the sponsor inspection lasted four days. One site inspected by FDA had inspectional observations.

Dr. Kim was cited for:

  • Failing to report adverse events in one subject (increased confusion and falls) to the sponsor
  • Reporting a serious adverse event (grade 3 hepatic hemorrhage) to the sponsor outside of protocol required timelines (approximately 3 weeks instead of within 24 hours)

Notable in the summary is that EMA inspected Dr. Tan and shared the results with FDA. FDA noted that the EMA had inspectional findings, but none that impacted acceptance of data from the site.

For the imaging review, FDA notes that the following were inspected: 

"The inspection focused primarily on assessing the accuracy of the tumor response and disease progression source records as it pertains to the contractual obligations of the CRO. Subject source documents/records generated by the CRO for 79 subjects from four clinical sites were compared to the eCRF and data listings. Assessment of conduct of the Charter-Specified CRO responsibilities included training, education, and qualifications of radiologists, correspondence with clinical sites/sponsor, quality assurance, data collection and management, computer system validation and Independent Review Charter review and adherence. "