adverse events

FDA Clinical Inspection Summary: Rhopressa (netarsudil) submitted by Aerie Pharmaceuticals, Inc.

FDA did not post any warning letters this week to Sponsors/Monitors/CROs, Clinical Investigators or IRBs. From the archives, here is the Clinical Inspection Summary for Rhopressa (netarsudil) submitted by Aerie Pharmaceuticals. Two sites were selected for inspection, based on enrollment and a large number of INDs listing the investigators (27 and 9) and no inspections or no inspections in the last twenty two years. Both sites received FDA Form 483s.

Dr. Cooke was cited for:

  • Failing to follow the investigational plan, specifically failing to repeat a test as directed by protocol for three patients
  • Assuming lab values were normal when a lab report was not available for one patient's visit

Dr. Logan was cited for:

  • Fourteen "transcription deficiencies" across eighteen patients' CRFs
  • Five instances of non-serious adverse events and concomitant medications not being captured in the CRF

Clinical Inspection Summary: IDHIFA (enasidenib) Submitted by Celgene

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 IDHIFA (enasidenib) submitted by Celgene. Three sites plus the sponsor were inspected. Site inspections ranged from three to five days and the sponsor inspection took place over 4 days. One site received a FDA Form 483.

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

  • Failing to report a headache and a fall in one subject that resulted in a visit to the emergency room.
  • Failing to report hospitalization for nausea and vomiting within twenty four hours as required by the protocol

Page 236 here has the data request showing information FDA expected within five days regarding sites to be potentially inspected. 

Page 127 here shows the FDA requiring analysis excluding subjects who did not have a positive result based on the companion diagnostic. 

FDA Clinical Inspection Summary: Baxdela (delafloxacin meglumine) submitted by Melinta Therapeutics

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 Baxdela (delafloxacin meglumine) submitted by Melinta Therapeutics. Two pivotal studies were submitted. Four sites plus the sponsor were selected for inspection. Site inspections ranged over four to twenty six days. The sponsor inspection took place over four days. Sites were selected for inspection based on participation in both studies, high enrollment, high contribution to efficacy and high rates of serious adverse events on study. Two sites received FDA Form 483s. 

Dr. Hansen was cited for:

  • Failing to document two adverse events in the CRF (facial eczema and injection site reaction)
  • Failing to report one prior therapy per protocol requirements

Dr. Overcash was cited for:

  • Failing to maintain adequate case histories, specifically
    • Failing to properly document adverse events in 34 out of 154 subjects reviewed
    • Failing to properly document the end date of concomitant medications in 4 out of 22 subjects reviewed
    • Failing to properly document medical history in 4 out 22 subjects
  • Failing to conduct the study per the investigational plan
    • Nine out of 154 subjects did not have their study Day 3 photographs taken twelve hours apart

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: 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