FDA Clinical Inspection Summary: Vizamyl submitted by GE Healthcare

FDA did not post any warning letters to Sponsors/Monitors/CROs, IRBs and Clinical Investigators this week. From the archives, here is the Clinical Inspection Summary from GE Healthcare. Of the five locations inspected, all were sponsor locations or sponsor vendors. 

The sponsor received a 483 for failing to monitor, specifically:

  • One site exceeded IRB-mandated enrollment limits without approval. Another site exceed the enrollment cap sixteen days before receiving approval to do so. 
  • The monitor failed to follow up when two sites did not submit the required IRB closure form
  • A subinvestigator performed two study related procedures (autopsy and geneotyping) and wasn't listed on the FDA Form 1572. At another site, one subinvestigator performed five autopsies and was not listed on the FDA Form 1572. 
  • Three subinvestigators at one site had not submitted financial disclosure forms.
  • At another site, two subinvestigators did not sign financial disclosure forms. FDA notes that aside from a one time reminder, the monitor did not follow up to collect the form for one subinvestigator. 
  • At one site, six of 10 ECGs were not performed within protocol specified timeframes

FDA Clinical Inspection Summary: Natpara submitted by NPS Pharmaceuticals

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 Natpara, submitted by NPS Pharmaceuticals. Three sites, plus the sponsor and CRO were inspected for the submission. Site inspections over from one to three weeks, the sponsor inspection was conducted over two months, and the length of time (as well as the identity) of the CRO is redacted in the publicly available documents. One site inspection was classified as "Official Action Indicated" (OAI); another site, the sponsor and the CRO received an inspection classification of "Voluntary Action Indicated" (VAI).

Dr. Bilezikian received a FDA Form 483 for the following:

  • The study coordinator forged the Principal Investigator(PI)'s  signature on the FDA Form s 1572.
  • The study coordinator forded the PI's signature on two Serious Adverse Event (SAE) reports.
  • The study coordinator forged 127 prescriptions (including for investigational product) related to the study.
  • The FDA inspector questioned the timing of the PI's signature on inclusion/exclusion criteria on source documents, as the signature was dated on Thanksgiving day, which was a holiday and the PI's appointment book did not contain any patient appointments on that day.
  • The study coordinator forged the PI's signature on the Investigator's Agreements.
  • FDA concluded that data from this site were unreliable.

Dr. Watts was cited for:

  • Failure to prepare and maintain adequate and accurate case histories, specifically in that one subject did not have four inclusion criteria documented in source documents.
  • FDA notes that the PI did not sign the paper source document, and signed 1-2 months late for other subjects.
  • FDA notes that the Electronic Data Capture System (EDC) did not capture two of the inclusion/exclusion criteria identified in a protocol amendment.
  • Three adverse events were marked as "moderate" in the paper source documents, but recorded as "mild" in the EDC. 

The Sponsor, NPS, was cited for:

  • Failing to bring a noncompliant investigator promptly into compliance
  • Failure to ensure proper monitoring
  • FDA notes that the CRO monitor was aware of signature irregularities in 2011 at Dr. Bilizekian's site, but a follow up meeting with the PI and monitor was held where the PI attested to the signatures in question. Due to the monitoring reports from 2011 and 2012, FDA disputes the sponsor's assertion that the irregularities were only discovered in 2014. 

The undisclosed CRO was cited for:

  • Failing to ensure proper monitoring of a study and failing to ensure that an investigation was conducted in accordance with the investigational plan.
  • FDA notes that the undisclosed CRO had purchased the original CRO responsible for the study and all but one person who had worked on the original study had left the company.


FDA Clinical Investigator Warning Letter

FDA did not post any warning letters to Sponsors/Monitors/CROs, IRBs or Clinical Investigators this week. From the archives, here is a clinical investigator warning letter issued in 2008.

Dr. Holub was warned for:

  • Failing to supervise the investigation
  • Failing to conduct the investigation according to the investigational plan, specifically:
    • Failure to assign subject screening numbers in compliance with the protocol
    • Failure to perform required screening assessments, including imaging
    • Enrolling a subject taking a prohibited concomitant medication
    • Failing to ensure that study personnel who were administering consent, dispensing study drug and determining eligibility were listed on the FDA Form 1572
  • Failing to maintain adequate records of investigational product, specifically:
    • Failing to distribute drug in compliance with subject randomization
  • Failure to ensure proper informed consent
    • Data was collected for one subject at a screening visit months before signing the IRB approved informed consent
    • Data was collected for another subject at a screening visit for another trial and used for the current trial. The subject did not sign the informed consent for the current trial until two months after data collection.
    • Another subject's consent form could not be located. The caregiver for the subject (this was an Alzhimer's trial) could not recall that the subject ever signed a consent.
  • Failure to retain required documents
    • FDA cites two missing consent forms
  • Failure to retain adequate and accurate case histories
    • Four missing case report forms
    • One subject was misidentified on a lab report

FDA notes that Dr. Holub indicated that the deficiencies were due to clinical research coordinators; FDA notes that it was the investigator's responsibility to oversee the trial.

FDA Clinical Inspection Summary for Pfizer's Ibrance

FDA did not post any warning letters this week to Sponsors/Monitors/CROs, IRBs or clinical investigators. From the archives, here is the inspection summary for Pfizer's Ibrance. One investigator received a 483. Although the eight pages of details around that five item 483 were redacted, in summary Dr. Fin was cited for:

  • Protocol Deviations
  • Discrepancies between source documents and CRF entires for adverse events, concomitant medications and doses of investigational product
  • Two subjects were not consented with the most recent IRB-approved Informed Consent. Three subjects were not reconsented as required by the IRB.
  • Investigational Product discrepancies with the number of doses taken by a single patient
  • The FDA Form-1572 was not updated to include two subinvestigators
  • One subject did not meet inclusion criteria
  • Two subjects were not randomized correctly
  • Laboratory safety assessments were not performed as required for six subjects
  • One serious adverse event was reported within 2 days instead of the 24 hours required by the protocol
  • Three subjects had pharmacokinetic samples collected out of window