Clinical Inspection Summary for Tesaro's Varubi

FDA did not issue any warning letters to Sponsors/Monitors/Contract Research Organizations (CROs), Institutional Review Boards (IRBs) or Clinical Investigators this week. From the archives, here is the clinical inspection summary for Tesaro's Varubi (rolapitant hydrocholoride). FDA inspected three of the Phase 3 studies included in the NDA submission, and one of the Phase 2 studies. The Phase 2 study had been conducted by the previous sponsor, Schering-Plough. Nine clinical sites across the four studies were inspected, plus the sponsor. Sites were selected for inspection on the basis on enrollment, efficacy and previous inspection history.

Dr. Jagiello-Gruzfeld received a 483 for:

  • Failing to follow the investigational plan
    • Failing to ensure that dosing was conducted according to protocol defined timelines
    • Failing to conduct follow up phone calls as required by protocol
  • Failing to maintain adequate and accurate case histories
    • One subject received expired drug

Dr. Fein received a 483 for failing to follow the investigational plan, specifically:

  • Failing to ensure that dosing was conducted according to protocol defined timelines
  • Three nurses who administered investigational product were not listed on the delegation of authority log.
  • One technician who collected blood samples was not listed on the delegation of authority log.
  • The time of drug administration was not documented for two subjects.

 

Dr. Salinas received a 483 for:

  • Failing to follow the investigational plan
    • Failing to ensure that dosing was conducted according to protocol defined timelines for ten of fifteen subjects enrolled.
    • One subject was enrolled with a source note by the principal investigator stating that the subject had received "a lot of chemotherapies" . FDA notes that the identity of these chemotherapies was not given, and further notes that prior cisplatin administration was an exclusion criteria for participation in the study.
  • Failure to prepare and maintain adequate and accurate case histories
    • Incorrect requisition forms were used for PK and clinical lab sample draws
    • White-out was used to change drug administration time
    • Pharyngitis and respiratory infection were not noted in the case report form (CRF) for one subject
    • Serious adverse events noted on laboratory results were not always reported to the sponsor in the specified time frame.
    • Chemotherapy logs were not completed as specified in the protocol.
    • There was no available source documentation to support that pharmacokinetic (PK) samples were handled as specified in the protocol.
    • Shipping records were not maintained to document the shipment of PK samples. FDA notes that some samples were not shipped for up to eight months after collection.
  • Inadequate informed consent, specifically that there was no statement that the FDA could inspect subject records.

Dr. Kowalski received a 483 for:

  • Failing to maintain adequate and accurate case histories
    • One subject's complaint of "dry heaves" was not recorded in the CRF
    • Two subjects' diaries documents that rescue medication were taken; however, there is no record that rescue medication were dispensed to these subjects.
    • One subject diary indicates that rescue medication was not taken; however, in the sponsor line listings this is listed as a missing value.
  • Failure to follow the investigational plan
    • Four serious adverse events were not reported in the timeframes required by the protocol. One report was seventy (70) days after the event.
    • The handwriting present in three subject diaries for the date and time of response to one question was observed to belong not to the subjects, but instead to study staff.

Dr. Urban received a 483 for inadequate records, specifically:

  • One informed consent was missing.
  • One randomization sheet was missing.
  • Two subject diaries had a blank response marked with regards to medication, but the sponsor line listings had this value as "No".

Dr. Font received a 483 for:

  • Failing to follow the investigational plan
    •  Failing to ensure that dosing was conducted according to protocol defined timelines for four subjects.
    • An adverse event of "unstable gait" was not recorded for one subject.
  • Failure to maintain adequate case histories, as there is no source document that specifies one subject's life expectancy and a life expectancy of greater than four months was a study inclusion criteria.

Dr. Suppaattagorn received a 483 for:

  • Failing to follow the investigational plan
    • FDA notes that a lack of training may have contributed to one subject receiving expired drug.
    • Subjects signed two consent forms, instead of receiving a copy of the signed consent form. FDA notes that there is no was to ensure that the second signed form was exactly the same as the one maintained at site. 

Dr. Gabrail received a 483 for failing to follow the protocol, specifically:

  • Three subjects did not meet inclusion criteria, including one that was enrolled on another clinical study.
  • Four subjects were dosed in timeframes different than what was outlined in the protocol.
  • Two subjects were included in the trial, despite having lab values outside of the inclusion criteria.
  • One subject was allowed to continue on the study despite not completing the required subject diary and not completing all protocol required procedures. 

Tesaro, the sponsor, was inspected and received a 483 for:

  • A noncompliant site was not brought into compliance promptly by the sponsor. FDA cites Dr. Kowalski's inspection described above, as well as another site. 

FDA also notes in the sponsor inspection that they reviewed one site's records specifically because a monitor had identified that the site was falsifying records, which led to the sponsor suspending the site and notifying the Polish Ministry of Health and IRB. Three other sites were selected for record review as part of the sponsor inspection because they were managed by a Site Management Organization (SMO), US Oncology, and there were concerns about principal investigator oversight and responsibilities. Finally, FDA notes that in the Phase 2 study conducted by Schering-Plough there were concerns about study blinding, as the actions taken by sponsor statisticians were not adequately documented and could not be provided during the inspection.