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.