concomitant medications

FDA Clinical Inspection Summary: Rhopressa (netarsudil) submitted by Aerie Pharmaceuticals, Inc.

FDA did not post any warning letters this week to Sponsors/Monitors/CROs, Clinical Investigators or IRBs. From the archives, here is the Clinical Inspection Summary for Rhopressa (netarsudil) submitted by Aerie Pharmaceuticals. Two sites were selected for inspection, based on enrollment and a large number of INDs listing the investigators (27 and 9) and no inspections or no inspections in the last twenty two years. Both sites received FDA Form 483s.

Dr. Cooke was cited for:

  • Failing to follow the investigational plan, specifically failing to repeat a test as directed by protocol for three patients
  • Assuming lab values were normal when a lab report was not available for one patient's visit

Dr. Logan was cited for:

  • Fourteen "transcription deficiencies" across eighteen patients' CRFs
  • Five instances of non-serious adverse events and concomitant medications not being captured in the CRF

FDA Clinical Inspection Summary: Verzenio (abemaciclib) submitted by Eli Lilly

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 Verzenio (abemaciclib) submitted by Eli Lilly. Six sites were selected for inspection, based on high site specific efficacy results, participation in numerous other trials, low numbers of protocol deviations, low numbers of reported Serious Adverse Events (SAEs) and low numbers of deaths on study. Inspections ranged from three days to three weeks. Two sites received FDA form 483s.

Dr. Dickler was cited for:

  • Failing to report adverse events to the sponsor, specifically five adverse events from three patients.
  • Failing to prepare and maintain adequate and accurate case histories.
    • Failing to report concomitant medications for four subjects. FDA notes that the monitor had informed the site at the start of the trial that recording this information was unnecessary. 
    • One adverse event did not have a toxicity grading.
    • The source for two concomitant medications was missing.

Dr. Salinas was cited for:

  • Failing to prepare and maintain adequate and accurate case histories.
    • FDA notes numerous discrepancies and only provides a few examples (three and a half pages) in the Clinical Inspection Summary.
    • For example, the radiology scan indicated a tumor was 10.6 mm, but the data listings indicated the tumor measured 100.6 and the source worksheet indicated a measurement of 106 mm.
    • Other examples include source worksheets indicated radiology scans were missed, but values for these scans were in the data listings.
    • Lesions had sizes of 4.9 mm in the data listings, but source worksheets indicated that they were too small to measure and data entry conventions stated that lesions too small to measure should have a value of 5.0 mm assigned.
    • Data listings indicated stable disease, the radiology report indicated progressive disease and the source worksheet had "None" entered for tumor response.
    • FDA notes that a sensitivity analysis should be performed, as the above listed errors impacted the primary endpoint for three patients at the site.

 

FDA Clinical Inspection Summary: Baxdela (delafloxacin meglumine) submitted by Melinta Therapeutics

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 Baxdela (delafloxacin meglumine) submitted by Melinta Therapeutics. Two pivotal studies were submitted. Four sites plus the sponsor were selected for inspection. Site inspections ranged over four to twenty six days. The sponsor inspection took place over four days. Sites were selected for inspection based on participation in both studies, high enrollment, high contribution to efficacy and high rates of serious adverse events on study. Two sites received FDA Form 483s. 

Dr. Hansen was cited for:

  • Failing to document two adverse events in the CRF (facial eczema and injection site reaction)
  • Failing to report one prior therapy per protocol requirements

Dr. Overcash was cited for:

  • Failing to maintain adequate case histories, specifically
    • Failing to properly document adverse events in 34 out of 154 subjects reviewed
    • Failing to properly document the end date of concomitant medications in 4 out of 22 subjects reviewed
    • Failing to properly document medical history in 4 out 22 subjects
  • Failing to conduct the study per the investigational plan
    • Nine out of 154 subjects did not have their study Day 3 photographs taken twelve hours apart

FDA Clinical Inspection Summary: Trulance (plecanatide) submitted by Synergy 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 Trulance (Plecanatide )s ubmitted by Synergy Pharmaceuticals. Two pivotal studies were submitted. Six sites, the CRO and the sponsor were selected for inspection. Site inspections ranged over four to fourteen days. The CRO inspection lasted 2 days and the Sponsor inspection lasted 4 days. Two sites received FDA Form 483s.

Dr. Valor was cited for failing to follow the investigational plan, specifically:

  • Eligibility violations for nine out of twenty one subjects (prohibited conmeds during pretreatment period, three subjects randomized despite exclusionary data recorded in the electronic patient diary, rescue medication taken during pretreatment period)
  • Seven subjects did not have post dose ECGs as required by protocol
  • Missing patient questionnaires at some study visits 

Dr Koltun was cited for:

  • Failing to document the number of tablets per kit returned to the sponsor at the end of the study

FDA Clinical Inspection Summary: Northera (droxidopa) submitted by Lundbeck

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 Northera (droxidopa) submitted by Lundbeck. Four sites were selected for inspection based on contribution to the efficacy of the study (i.e., the study would not have had a positive result if a site was excluded), large treatment effect compared to other sites, adverse events and number of patients excluded from either the per protocol analysis set or full analysis set. Inspections ranged from three to eleven days. Two sites received FDA Form 483s.

Dr. Gil was cited for:

  • Failing to follow the investigational plan, specifically:
    • EKGs were signed by the Principal Investigator up to 7 months late
    • Failing to perform a protocol specified test within the post-dosing timeframe required by the protocol
  • Failing to prepare and maintain adequate and accurate case histories, specifically:
    • One study coordinator signed off on study form stating s/he performed two assessments that were actually performed by a different study coordinator
    • The investigator signed off on a verification of eligibility form which did not have any questions answered regarding a subject's eligibility and the signature was not dated
  • Inadequate investigational product accountability records, specifically:
    • One subject received investigational product from a different study
    • The study coordinator recorded one subject's medication adherence as 80%, but source records indicated that it was 50%

Dr. Lisk was cited for:

  • One subject was enrolled with diabetic neuropathy against protocol eligibility criteria. FDA did not accept the investigator's position that diabetic peripheral neuropathy differed from diabetic autonomic neuropathy. FDA also notes that this patient was not included in the per protocol analysis.
  • Two subjects did not maintain stable concomitant medication doses as required by protocol. FDA notes that the protocol was not clear, but states that the investigator should have sought clarification from the sponsor.
  • The investigator up-titrated a subject's dose of investigational product, which was not permitted by the protocol.