FDA did not issue any warning letters to Sponsors/Monitors/CROs, IRBs or Clinical Investigators this week. From the archives, we can look at the Clinical Inspection Summary of the five studies submitted to FDA in support Vraylar (cariprazine hydrochloride) by Forest Laboratories. FDA provided the following detail regarding site selection for inspection: multiple studies conducted at each site, adequate representation of both studies at each site, high enrollment and no/remote FDA inspection history. FDA selected three Ukranian sites for inspection because the efficacy response at these sites was three times higher than the US sites. Eight sites plus the sponsor were inspected. The longest inspection ranged over a month, and one site had two inspections. Three sites plus the sponsor inspection were classified as "Voluntary Action Indicated" and one site was classified as "Official Action Indicated".
Dr. Burtner received a 483 for:
- Two subjects who met exclusion criteria were randomized to the study.
- Failing to assign randomization numbers in the order specified by the protocol for three subjects.
- Late informed consent for genotyping of subject samples.
- CRF entries were made without supporting source documentation. FDA notes that the study coordinator responsible for this had their employment terminated.
- Study assessments were performed by unqualified (untrained) personnel.
- Fourteen adverse events were not reported to the IRB or sponsor.
Dr. Sokolowski received a 483 for:
- Three subjects met exclusion criteria but were enrolled.
- Three subjects did not meet inclusion criteria but were enrolled.
- Three subjects were given dose increases, despite achieving a treatment response.
- Ten subjects were given doses of lorezpam above protocol limits.
- Seven subjects received prohibited concomitant medications.
- PK samples were collected up to eight hours later than protocol requirements for five subjects.
- Two subjects had PK samples collected earlier than protocol requirements.
- Data discrepancies on an assessment scale did not match between the source and the CRF for five subjects.
- Data discrepancies were noted between severity and relationship of adverse events as recorded on source documents and in the CRF.
- Six laboratory values were considered not clinically significant and were not recorded as adverse events.
- Three capsules dispensed to one subject were not accounted for.
- Records indicated that one subject took ten more capsules than were dispensed.
Dr. Kwentus received a 483 for:
- Four subjects did not meet eligibility criteria.
- Two hundred and thirteen (213) adverse events and medications administered were not reported across 18 patients in three studies. FDA notes that in a meeting with the sponsor it was disclosed that many non-serious adverse events and associated concomitant medications were not reported across the studies and that the sponsor would be submitting additional analysis for review.
- FDA notes that the safety data submitted by this site for one study may be unreliable.
Dr. Moroz received a 483 for:
- Severity and relatedness of two adverse events to study therapy were inconsistent between the source and CRF.
- One positive drug screen for barbiturates was reported, but no source documentation was present.
- One urinalysis was not done for one subject as required by protocol.
The sponsor, Forest Laboratories, received a 483 for:
- Failing to finalize the monitoring plans in the timelines specified by standard operating procedures (SOPs).
- Forty positive drug screens for subjects enrolled across three studies were not reported in the NDA line listings.
- Eight subjects were not listed in an NDA line listing for medication administration.
- One subject who did not meet eligibility criteria was not listed in the NDA line listing of eligibility criteria violations.
- Subinvestigators at three clinical sites did not submit end of study Financial Disclosure Forms in the required timeframes.
In addition to the FDA 483 observations noted above, FDA also discussed the following with the sponsor:
- Not all data for 5 subjects at one site was source verified.
- One site had monitoring visits outside the timeframe required by the sponsor's SOP.
- Monitoring reports for four sites were not finalized in the timeframe required by SOP.