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.

FDA warning letter to Monmouth Medical Center IRB

FDA posted a warning letter to an Institutional Review Board (IRB) this week. Monmouth Medical Center IRB was warned for:

The IRB responded to the FDA 483, but the warning letter notes that the response was unacceptable due to the lack of:

  • The IRB’s subpart D determination for one of the protocols cited in the warning letter
  • A finalized copy of the IRB meeting supplemental form
  • A finalized copy of the IRB checklist used for evaluating pediatric studies
  • Any relevant Standard Operating Procedures (SOPs) that have been revised
  • A projected timeline for the implementation of any new SOPs
  • A description of any training provided to the IRB staff and members on the new SOPs
  • A list of staff and members trained
  • A projected timeline of planned training

FDA Clinical Inspection Summary for Kanuma (sebelipase alfa) submitted by Alexion (acquired from Synageva)

FDA did not issue any warning letters to Clinical Sponsors/Monitors/CROs, IRBs or Investigators this week. From the archives, here is the clinical inspection summary for Kanuma (sebelipase alfa) submitted by Alexion. This therapy was acquired from Synageva. Two pivotal studies were submitted to FDA, from which four sites, three CROs and the sponsor were selected for inspection. Site inspections were based on high enrollment and participation in more than one study. The CROs were selected due to the importance of MRI readings and liver histopathology analysis to the efficacy analysis. The sponsor was selected because this Biologics Licensing Application was for a new molecular entity. Site inspections ranged over four to eight days, and the sponsor inspection took place over six days. No Form FDA-483s were issued to clinical sites. 

Synegeva received a 483 for failure to ensure that an investigation was conducted in accordance with the general investigational plan and protocols as specified in the IND, specifically:

  • Failing to ensure that serious adverse events at one site were reported to the sponsor within 24 hours, as required by protocol. 

Sponsors are permitted to redact a great deal of information in publicly available inspections for CROs. However, it may be useful to note the specific areas covered in the inspections for the CROs on these two trials: 

  • Quality Assurance
  • Quality Control
  • Subject Masking
  • Process Flows
  • Organizational Responsibilities
  • Operating procedures for imaging and pathology
  • Training of staff
  • System validation
  • Correspondence between the CRO, Sponsor, Clinical Sites and sub-contractors
  • Validation of subject data points
  • Protocol deviations
  • Data storage
  • Work Orders
  • Service Agreements

It is also notable that FDA made inquiries to the sponsor regarding blinding of the trial, apparently in the same time frame as the inspection of the CROs. The sponsor submitted an erratum to the Clinical Study Report further clarifying the blinding issue.

FDA Clinical Inspections for alirocumab by Sanofi-Aventis

FDA did not post any warning letters addressed to Sponsors/Monitors/Clinical Research Organizations (CROs), Institutional Review Boards (IRBs) or Clinical Investigators this week. From the archives, let's have a look at the BIMO clinical inspection summary for PRALUENT® (alirocumab) by Sanofi-Aventis and Regeneron.

Four studies were included in the inspections for this Biologics License Application (BLA). Fourteen sites were inspected, along with a vendor and the sponsor. Site inspections were conducted over periods of time ranging from two days to two weeks. The sponsor inspection took place over eleven days. 

Dr. Ginsberg received a 483 for: 

  • Failing to follow the investigational plan
    • Failing to perform a serum pregnancy test as required by protocol on a 44 year old female subject. FDA notes that a urine pregnancy test was performed.
    • A lipid sample required by protocol was not done for one subject at a week 78 visit
    • A week 8 urine sample was discarded for one subject instead of being sent to the lab
    • A visit twelve blood pressure for one subject was done in the supine position instead of sitting
  • Failing to report adverse events. FDA notes that the investigator did not consider these lab abnormalities to be adverse events.
    • One out of range urine white blood cell count for one subject
    • One out of range Gamma-glutamyl transferase (GGT) value for one subject
  • Failure to prepare or maintain adequate and accurate case histories
    • The Eligibility Inclusion and Exclusion criteria for all 14 enrolled subjects were reviewed by an Investigator after randomization had occurred.
    • The 12-lead Electrocardiograms (ECG's) taken during four of the enrolled subjects' screening visits were reviewed by an Investigator after randomization had occurred. 

Dr. Koren received a 483 for:

  • Enrolling a subject that did not meet inclusion/exclusion criteria. FDA notes that although rescreening was permitted for some labs, the lab in question was not one that was allowed for rescreening.
  • Conflicting source records for an excluded concomitant medication at screening.

Dr. Zuzarte received a 483 for:

  • Enrolling three ineligible subjects. FDA notes that an stratification error in randomization was identified but could not be fixed by the system.

Dr. Horvathova received a 483 for:

  • Randomizing five subjects prior to confirming inclusion/exclusion criteria for blood pressure. FDA notes that one subject was ineligible.
  • Drug accountability discrepancies compared to patient diaries for three subjects. FDA notes that this was due to a former employee completing records based on phone calls with subjects without properly attributing this information in the source.

Other interesting items to note from this inspection summary:

  • FDA notes that the "confusing" CRF led to randomization and stratification errors, but did not write a 483. 
  • At the sponsor inspection, FDA reviewed issues that led to randomization errors and noted that corrective and preventative actions (CAPAs) were put in place.
  • FDA notes that the failure of the sponsor to review lab data transfer specifications led to patients not being properly titrated. FDA notes that there were no safety issues associated with this, and also notes the steps the sponsor took to prevent this issue in the future.
  • The sponsor had to conduct sensitivity analysis to determine the effect of stratification errors.
  • The sponsor had distributed an unvalidated electronic lipid calculator tool to aid with eligibility determination of some subjects. FDA noted that more information was required to determine the appropriateness and validity of this tool.
  • FDA had the sponsor conduct activities post-submission to determine the level of unblinding of sites who ordered local labs instead of central labs. The sponsor had to do additional sensitivity analyses to determine if this issue affected the study results.

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