pregnancy

FDA Clinical Inspection Summary: Zykadia (ceritinib) submitted by Novartis

FDA did not post any warning letters to clinical trial Sponsors/Monitors/CROs, IRBs or Clinical Investigators this week. From the archives, here is the Clinical Inspection Summary for Zykadia (ceritinib) submitted by Novartis. Three sites, a vendor and the sponsor were inspected. Site inspections ranged from eight days to one month. One site and the sponsor received FDA Form 483s.

Dr. Mehra was cited for:

  • Failing to follow the investigational plan, specifically:
    • Enrolling one subject that did not meet specific study inclusion criteria
    • Failing to enter tumor assessment measurements into the eCRF for one subject at one cycle visit
    • Failing to perform five ECGs as required by protocol

The sponsor was cited for:

  • Failing to properly monitor the study, specifically:
    • Failing to report all protocol deviations in line listings (14 missed pregnancy tests for five subjects at three sites)
    • Two missing monitoring visit reports for one site

Clinical Inspection Summary: Byvalson (nebivolol hydrochloride; valsartan) submitted by Forest Labs

FDA did not post any warning letters this week to Sponsors/Monitors/CROs, IRBs or Clinical Investigators. From the archives, here is the Clinical Inspection Summary for Byvalson (nebivolol hydrochloride; valsartan) submitted by Forest Labs. Three sites were selected for inspection. Two were selected on the basis of high enrollment and high treatment effect size, as well as a number of previous trials (13 and 5 respectively) with no previous FDA inspections. The third site was selected due to high enrollment, as well as a sponsor complaint on a different trial five years ago and a previous FDA inspection with a 483. Site inspections ranged from 3 to 14 days. Two sites received FDA Form 483s.

Dr. DiGregorio was cited for failure to follow the investigational plan, specifically:

  • Failing to use the local laboratory urinary drug screen results to randomize five subjects, as required by the protocol. (FDA notes that central laboratory results were used.)
  • Failing to use serum pregnancy results from the central laboratory to randomize four subjects as required by the protocol.
  • Failing to perform vital sign measurements on the day of randomization for three subjects as required by the protocol.
  • Failing to perform hematology labs on the day of randomization for one subject.
  • Failing to perform end of treatment pregnancy testing for one subject.
  • Administering increased doses to six subjects one day earlier that the protocol permitted.
  • Failing to perform protocol required follow up for one subject who had a prolonged QTc interval at the End of Treatment Visit.

Dr. Lara was cited for the following:

  • Failing to follow the investigational plan by randomizing three ineligible subjects (one had a history of gastric bypass, one had a right bundle branch block evident in the ECG and one had an out of range ECG value at screening).
  • Failing to report to the IBR the three ineligible subjects who were randomized. 

FDA Clinical Inspection Summary: Oritavancin submitted by the Medicines 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 Orbactiv (oritavancin) submitted by the Medicines Company. Five sites plus the sponsor were selected for inspection of the two pivotal trials submitted. Site inspections ranged over one to three weeks and the Sponsor inspection took place over one week. Four sites received FDA form 483s.

Dr. Kabler was cited for:

  • Failing to ensure proper storage of study drug due to multiple temperature excursions of the refrigerator where drug was stored.
  • Failing to report two adverse events noted in source documents in the electronic Case Report Form (CRF).
  • The CRF indicated that due to a fever one subject could not be considered a clinical success but the source document had not been updated to reflect this. 

Dr. Porwal was cited for:

  • Failing to report thirty protocol deviations in the clinical database. FDA notes that Dr. Porwal's response stated that the study coordinator had identified these items prior to the closeout visit at which point the database was locked and the deviations could not be entered.

Dr. Keech was cited for failing to comply with the protocol, specifically:

  • Enrolling a subject with ineligible lab values.
  • Failing to perform a protocol required blood test for HbA1C at the baseline visit for a subject with high glucose values. 
  • Failure to report a mild adverse event at the injection site for one subject.
  • Three out of range lab values were not reported as adverse events. FDA notes that the protocol was ambiguous with regards to report laboratory abnormalities as adverse events, and notes that assessment of laboratory results would take place by the FDA safety reviewer.

Dr. Manos was cited for:

  • Failing to perform protocol required lab tests on five separate occasions. FDA notes that this was due to a study coordinator revising the source document worksheets.

FDA did not issue a 483 to the sponsor, but notes that two items were noted during the inspection. One site had been discontinued from the study and reported to the FDA for enrolling one subject with inconclusive pregnancy results who was later found to be pregnant and another who had exclusionary liver function tests. The site had also failed to submit lab tests to the central lab for three subjects and performed the tests locally only.