Medicines Company

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.

Clinical Inspection Summary for cangrelor by the Medicines Co.

FDA did not post any warning letters to Sponsors/Monitors/CROs, IRBs or Clinical Investigators this week. From the archives, let's have a look at the inspection summary for Kengreal cangrelor ), submitted by  the Medicines Company for priority review. Five sites, four foreign and one domestic, were selected for inspection based on enrollment and efficacy results. All BIMO inspections were 3-4 days long. One site received a 483.

Dr. Shaburshivili did not receive a 483, but minor recordkeeping issues were noted in the inspection, specifically:

  • One study completion page lacked a subject number
  • One randomization worksheet was not signed
  • One checkbox was not marked yes on one subject's end of study form
  • Four subjects had inconsistencies with their date of birth information
  • Several subjects had incorrect initials
  • Note: A sponsor rep was present during the inspection, and answered questions about adjudication of cardiac events

Dr. Kabeishvili was inspected and did not receive a 483. FDA noted the following during the inspection:

  • Three subjects had the incorrect angiograms uploaded initially, the FDA inspector noted that this was corrected during the study
  • Two pairs of subject angiograms were swapped at initial upload, the FDA inspector verified that this was corrected during the course of the study
  • One subject had two different dates of birth in study documentation
  • One subject had incorrect initials in study documentation
  • A follow up phone call visit form was not signed

Dr. Tousek was inspected, and received a 483 for:

  • Failure to report adverse events to the sponsor
    • Two subjects had a hemoglobin change outside protocol limits
    • Five events (atrial fibrillation, hematoma, back pain, oozing and agitation) in five subjects within 48 hours of the procedure

FDA also noted the following from the inspection at Dr. Tousek's site:

  • Four laboratory forms were missing required demographic information
  • An incorrect date was given for one subject for the 30 day follow up visit
  • The 48 hour form was not completed for one subject
  • Two ineligible subjects were enrolled, and FDA notes that this was included in the sponsor's line listings

Dr. Steinwender was inspected and did not receive a 483. FDA notes that Dr. Steinwender was not the initial Principal Investigator for the trial.  FDA noted the following from the inspection:

  • Four subjects did not have a repeat test, as required by protocol. FDA notes that this was at the beginning of the study, and that the monitor brought this to the sites attention.
  • Five subjects did not have a hematology test drawn the day after the procedure. FDA notes that this was at the beginning of the study, and that the monitor brought it to the attention of the site, and the site subsequently corrected the issue.
  • One subject was missing an ECG printout
  • Source records for two subjects failed to document the Plavix prescription at discharge, that was recorded in the case report form (CRF) and sponsor data listings.

Dr. Spriggs was inspected and did not receive a 483. FDA noted the following from the inspection:

  • One subject was enrolled and received study drug prior to exclusionary INR results being received