FDA Warning Letter: Entellus Medical

FDA posted a warning letter this week to a device sponsor. 

Entellus Medical was warned for:

  • Failing to secure compliance of noncompliant investigators
    • FDA notes that sponsor employees were present at procedures that did not comply with the approved trial protocol
    • FDA notes that the eighteen pre-planned protocol violations were not reported to FDA
  • Failing to receive FDA and IRB approval prior to implementing a change to the investigational plan
    • FDA states that the pre-planned protocol deviations were encouraged
    • FDA notes that the pre-planned protocol deviations were documented in monitoring visit reports
  • Failing to notify the FDA and IRB of significant new information
    • FDA notes that FDA was notified of the protocol deviation upon submission of the Annual report
    • FDA notes that the IRB was notified after the FDA inspection
  • Failing to submit changes in the investigational plan to the FDA and IRB prior to implementation
    • FDA states that study subjects were placed at an increased risk of harm

FDA Clinical Inspection Summary: Austedo (deutertabenazaine) submitted by Teva

FDA did not post any warning letters to Sponsors/Monitors/CROs, Clinical Investigators or IRBs this week. From the archives, here is the Clinical Inspection Summary for Austedo (deutetrabenazine) submitted by Teva. Two of the thirty participating sites in the study were selected for inspection based on high enrollment and impact on decision making for approval. FDA notes that a statistical methodology was used for site selection. Site inspections ranged over four to eighteen days. One site received a FDA Form 483.

Dr. Claassen was cited for:

  • Two subjects were unable to provide a required blood sample at one visit and the site made arrangements for them to return another date to provide the sample. (Note: The FDA reviewer indicates that the inability to draw blood is understandable and that the action taken in response to the protocol deviation was acceptable.)
  • One subject's medical records indicated excessive alcohol consumption and an attempt to reduce alcohol intake to six beers a week, plus marijuana use on Fridays. FDA notes that this marijuana and alcohol use violate two of the eligibility criteria for the study.
  • Study records for one subject indicated no alcohol use at screening, but two months after screening this was changed to indicate alcohol use. Additionally, three months after screening the amount of alcohol used per week was changed from 1 beer per week to four beers per week with no explanation. 

Note: FDA meetings with the sponsor indicate a concern about alcohol's effect on the activity of the study drug. Study exclusion criteria addressed this.  

The other site that was inspected did not receive a FDA Form 483, but the inspection summary notes issues of prepopulation of some forms to "save time", write overs and inadequate source documentation for some visits. 

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: Adempas submitted by Bayer Healthcare Pharmaceuticals

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 Adempas submitted by Bayer. Four sites plus the sponsor were selected for inspection. Sites were selected based on risk, including high enrollment on other FDA trials, low variability of subject blood pressure measurements between visits, large improvements in overall efficacy for subjects. Site inspections lasted four days; the sponsor inspection lasted over two weeks. One site and the sponsor received an inspection classification of "Voluntary Action Indicated" and an FDA Form 483,

Dr. Jing was cited for failing to follow the investigational plan. The study manual required the investigator sign the catheterization printouts and tracings, and this was not done. 

Bayer was cited for failing to ensure proper monitoring, including specifically failing to include the following protocol deviations in the clinical study report:

  • Enrolling two subjects who exceeded the age range for the study. (FDA notes that the protocol was later amended and the patients would have been eligible after the amendment, but was not eligible at the time of enrollment.)
  • Four subjects did not meet eligibility criteria for one parameter (pulmonary vascular resistance). FDA notes that these deviations were noted as "minor" in meeting minutes, but were not included in the Clinical Study Report. 
  • A certificate of analysis was sent to one site that was potentially unblinding to the site. 
  • One subject followed site instructions and took the wrong dose of medications for nine days. 
  • There were thirteen instances where drug accountability logs, number of pills returned and eCRF entries did not match. FDA notes that the monitor did not identify these issues during monitoring.