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





FDA Clinical Inspection Summary: Entresto by Novartis

FDA just posted the clinical inspection summary for Entresto by Novartis. Out of 984 sites worldwide, four sites were selected for high enrollment and high efficacy results in the treatment arm. Site inspections ranged from three to eleven days. Novartis also hosted a sponsor inspection that spanned two weeks. 

Dr. Aggaral in India was inspected by an FDA BIMO inspector, and although the inspector noted a failure to report minor protocol deviations, no 483 was issued.

Dr. Botelho in Brazil was inspected, and was issued a one item 483 failure to follow the investigational plan, specifically:

  • An adverse event of abdominal cramping and diarrhea was recorded in source records, but not reported to the sponsor.
  • Eighteen of twenty two source records reviewed contained concomitant medications that were not reported to the sponsor. 
  • Note: the FDA OSI reviewer flags this for the review division to consider regarding the safety and efficacy analysis.

Dr. Li in China was inspected, and received a 483 for failure to prepare and maintain accurate case histories, specifically the following adverse events:

  • Failure to report a hospitalization for a transient ischemic attack (TIA)
  • Failure to report bronchitis that occurred during a hospitalization for a myocardial infarction (MI)
  • Failure to report edema in one subject
  • Note: the FDA OSI reviewer recommends that the review division may wish to include the unreported adverse events in the safety analysis

Dr. Staneva in Bulgaria was inspected. FDA did not issue a 483, but noted an improvement in study record keeping once a new Principal Investigator (PI) and monitor were assigned.

FDA did not issue a 483 to Novartis during the sponsor inspection. FDA notes that Novartis had closed four clinical trial sites for GCP issues identified during monitoring, compromised data integrity discovered during an audit and inconsistencies identified in informed consents. During the BIMO inspection, FDA also looked at the operation and documentation of the Data Monitoring Committee (DMC) and adjudication committees. The inspector reviewed the transfer of obligations between Novartis and a vendor, as well as the Standard Operating Procedures (SOPs) for monitoring, protocol deviation reporting and monitoring. The inspection summary also reveals that FDA dug pretty deeply into investigational product management.