unblinding

FDA Clinical Inspection Summary: Adempas submitted by Bayer Healthcare Pharmaceuticals

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 Adempas submitted by Bayer. Four sites plus the sponsor were selected for inspection. Sites were selected based on risk, including high enrollment on other FDA trials, low variability of subject blood pressure measurements between visits, large improvements in overall efficacy for subjects. Site inspections lasted four days; the sponsor inspection lasted over two weeks. One site and the sponsor received an inspection classification of "Voluntary Action Indicated" and an FDA Form 483,

Dr. Jing was cited for failing to follow the investigational plan. The study manual required the investigator sign the catheterization printouts and tracings, and this was not done. 

Bayer was cited for failing to ensure proper monitoring, including specifically failing to include the following protocol deviations in the clinical study report:

  • Enrolling two subjects who exceeded the age range for the study. (FDA notes that the protocol was later amended and the patients would have been eligible after the amendment, but was not eligible at the time of enrollment.)
  • Four subjects did not meet eligibility criteria for one parameter (pulmonary vascular resistance). FDA notes that these deviations were noted as "minor" in meeting minutes, but were not included in the Clinical Study Report. 
  • A certificate of analysis was sent to one site that was potentially unblinding to the site. 
  • One subject followed site instructions and took the wrong dose of medications for nine days. 
  • There were thirteen instances where drug accountability logs, number of pills returned and eCRF entries did not match. FDA notes that the monitor did not identify these issues during monitoring. 

FDA Clinical Inspection Summary: Neutroval (XM02) submitted by Teva Pharmaceuticals

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 Neutroval (XM02) submitted by Teva Pharmaceuticals. Two sites, the sponsor (Biogenerix AG) and a CRO were inspected. Site inspections lasted 3-5 days. Both sites and the sponsor were issued FDA Form 483s.

Dr. Zabarskaya was cited for the local lab using hematology analyzers to analyze samples where the results report stated that the reagents used may be expired. 

Dr. Makhson received a citation for failing to have on file documentation indicating that quality control procedures for the hematology analyzers were in place for two years during the study. 

Biogenerix AG was inspected in conjunction with the CRO and was cited for:

  • Failing to conduct the investigation according to the investigational plan, specifically:
    • There were no written records to support unlocking the database twice following unblinding (including a lack of date for the second unlocking) by the CRO
    • Sponsor approval was not obtained for unlocking the database as required by SOP (note the Form 483 was issued to the sponsor)
    • Failing to have a CRO signature on the first unlock form (note this was in the 483 issued to the Sponsor)
    • No database unlock form was available for the second unlock
    • A project manager signature was added to one of the unlock forms retrospectively and backdated with an explanation
    • Database quality control forms were not maintained as required by SOP, including QC checks and randomization for final QC checks