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.
- 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.