Monitoring

FDA Clinical Inspection Summary: Calquence (acalabrutinib) submitted by Acerta Pharma

FDA did not post any warning letters this week to Sponsors/Monitors/CROs, IRBs or Clinical Investigators. From the archives, here is the recently posted clinical inspection summary for Calquence (acalabrutinib) submitted by Acerta Pharma. Two sites (out of forty participating in the trial )plus the sponsor were inspected. Site inspections lasted two and five days. Sites were selected on the basis of high enrollment and potential contribution to efficacy. The sponsor inspection lasted two weeks.

The sponsor received a FDA Form 483 for failing to monitor the study properly, specifically:

  • Failing to ensure sites submitted protocol amendments to the IRB in a timely fashion. Delays were noted to be four to eleven months. 
  • Failing to assure investigators and subinvestigators documented training.

FDA Clinical Inspection Summary: Tymlos (abaloparatide) submitted by Radius Health

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 Tymlos (abaloparatide) submitted by Radius Health. Four sites plus the sponsor were inspected. Sites inspections ranged over 8 to 12 days and the sponsor inspection ranged over 8 days. The sponsor received a FDA Form 483.

Inspection criteria for sites included the following:

  • High percentage of screened patients meeting enrollment criteria
  • Low rate of non-serious adverse events reported compared to other trial sites
  • No history of FDA inspections
  • High number of enrolled subjects
  • Minimal history of experience as a Principal Investigator
  • Rate of missing data within the datasets submitted to FDA
  • Location of the site within a non-ICH region

Radius was cited for:

  • The transfer of regulatory obligations (TORO) to the Contract Research Organization was not described in writing. Work statement plans for pharmacovigilance, clinical monitoring and clinical study management were not finalized until after the study started.
  • Failing to monitor the study properly, specifically three sites began screening patients prior to the monitoring guidelines being finalized and one site randomized a subject prior to being monitored. 

FDA Inspection Summary: Bavencio™ (avelumab) submitted by EMD Serono

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 Bavencio (avelumab) submitted by EMD Serono. Four sites, the vendor responsible for the independent review committee of the study endpoint and the sponsor were inspected. Site inspections ranged from four to fourteen days, the vendor inspection lasted four days and the sponsor inspection ranged over eight days. Two sites plus the sponsor received FDA Form 483s.

Dr. Bhatia was cited for:

  • Failing to report a Serious Adverse Event (SAE) to the sponsor in the protocol required timeframes
  • Three subjects missed 20% of the protocol required post-infusion ECGs. (FDA notes that the site identified root cause of these missed ECGs and implemented a corrective action plan during the course of the inspection.)

Dr. Shih was cited for:

  • Failing to report adverse events per protocol, specifically 50 non-serious adverse events were not reported from the site to the sponsor.
  • Failure to administer protocol required premedications for two subjects

EMD Serono received a 483 for:

  • Failing to monitor the study properly, specifically one monitor failed to report five protocol deviations at one site relating to subjects not receiving protocol required premedications.
  • Failing to follow the investigational plan, specifically:
    • Failing to finalize the Clinical Operations Plan for the study until one year after the first subject was enrolled. This plan included site selection and monitoring. 
    • A SUSAR report was received at the CRO, but not submitted to FDA or other investigators for one month. 

FDA Clinical Inspection Summary: Pomalyst (pomalidomide) submitted by Celgene

FDA did not post any warning letters this week to Sponsors/Monitors/CROs, IRBs or Clinical Investigators. From the archives, here is the Clinical Inspection Summary for Pomalyst (pomalidomide) submitted by Celgene. Three sites plus the sponsor were selected for inspection based on the submission of a single Phase 1/2 study. Site inspections ranged from six to twenty days and the sponsor inspection ranged over one month. One site and the sponsor received an FDA Form 483.

Dr. Siegel was cited for failing to maintain adequate investigational product accountability. Specifically, the records for three subjects did had discrepancies of two to five capsules. 

Celgene was cited for the following:

  • Inadequate monitoring of the study
    • The monitoring plan required investigational product accountability to be performed at every visit.
    • FDA review of monitoring visit reports determined that for three sites investigational product accountability was done at half or less than half the visits.
    • Four monitoring visit reports lacked a description of investigational product accountability activities by the monitor at the visit. 
    • Investigational product accountability records lacked lot numbers and quantities of investigational product destroyed by a third party. 
  • Inadequate labeling of investigational product
    • The investigational drug labeling lacked directions to the patient to take at least two hours before or after eating. 

FDA Sponsor-Investigator Warning Letter

FDA posted a warning letter this week to a Sponsor-Clinical Investigator. 

Dr. Burt was warned for:

  • Failing to ensure that the study was conducted in accordance with the investigational plan in the IND, specifically:
    • Failing to report Grade 3 adverse events in two subjects at one site to FDA in annual reports, as required by the protocol.
    • Failing to ensure four sites reported adverse events, as required by the protocol. FDA notes that there was no adverse event CRF designed for the study.
    • Failing to report two deaths on study to the FDA as required by the protocol.
    • Failing to review three adverse events during the course of the study to determine if they required reporting to FDA
    • Failing to conduct the interim analyses required by the protocol.
  • Failing to submit a protocol amendment to the IRB
    • The protocol was amended when new investigators were added to the study, but these three protocol amendments were not submitted to FDA
    • A total of nine protocol amendments were not submitted to FDA
  • Failing to select qualified investigators
    • The sponsor investigator was unaware of the training and qualifications of one site and eventually that one site was suspended from the trial for enrolling ineligible subjects.
    • The stated selection criteria for three other sites was "knowledge of professional reputation"
  • Failing to obtain CVs, Financial disclosure and FDA 1572s from participating sites.
  • Failing to provide an investigator brochure.
  • Failing to monitor study progress
    • No onsite monitoring was performed
    • There was no evidence of other types of monitoring
  • Failing to submit annual reports
  • Failing to review adverse events at his own site, as required by the protocol.
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