NI A. KHIN, M.D.

1
CLINICAL INSPECTION SUMMARY

• NI A. KHIN, M.D.
• Medical Officer
• Division of Scientific Investigations
• Office of Medical Policy
• Food and Drug Administration

2
TYPE I EVENT

• Occurrence of a significant suicide
  attempt (including completed suicide) or
• Hospitalization due to imminent suicide risk
  (including increased level of surveillance)
• As confirmed by the Suicide Monitoring Board (SMB)

3
CONCERN

• Potential Bias
• The unblinded investigators at each site
  apparently had the final say whether or not a
  particular event would be referred to the SMB

4
PURPOSE

• An audit of clinical records for a sample of
  subjects on clozapine for whom events were not
  referred to suicide monitoring board in order to
  determine definitively whether or not potential
  events were ignored for subjects assigned to
  clozapine (non-referrals)
• Selected centers with high rates of non-referrals
  to the SMB among clozapine-treated subjects

5
INSPECTIONAL OBSERVATIONS

• Center A
• 12 subjects
• Source Documents progress Notes, hospital notes
  (ER, C/L, In-pts)
• Interviewed PI, unblinded psych coordinator
  blinded psych left center
• 4 subjects completed the study
• 8 subjects discontinued during the study

• Center B
• 10 subjects
• Source Documents progress Notes (work sheet),
  hospital notes
• Interviewed blinded psych PI out of country,
  unblinded psych and coordinator left
• 5 subjects completed the study
• 5 subjects discontinued during the study

6
INSPECTIONAL OBSERVATIONS

• Center A
• Of 8 Subjects discontinued
• 1 at wk 96 (went to another OPD, switched to
  olanz.) lost f/up 500 mg dose day 664
• 1 at wk 54 (2 hospitalization abd. Cramp, r/o HIV
  enceph switched to risperid. haldol) LOE 100
  mg day 379
• 1 at wk 3 (pt decision) wc day 11
• 1 no show (certified mail return) lost f/up day
  316
• 1 lost f/up at wk 18 wc day 125
• 1 at wk 3 no show lost f/up day 14
• 1 at wk 1 (no PN) wc
• 1 arrested at wk 7 admin. day 46

• Center B
• Of 5 subjects discontinued
• 1 at wk 98 (2 ER visits during study switched
  to olanz. at d/c) wc 200mg day 682
• 1 at wk 4 (hospitalized psychosis exacerbation
  ER, RN, med student, intern, resident, attending
  notes contacted subj, no wish to continue) wc
  100mg day 21
• 1 at wk 56 (bld gluc, sedation during study) PV
  100mg day 394
• 1 at wk 1 (no show) lost f/up day 8
• 1 at wk 6 (sedation, refused Rx) wc 75 mg day
  48

Note wc (withdrew consent) pv (protocol
violation) LOE (lack of efficacy) lost f/up
(lost to follow up)
7
INSPECTIONAL SUMMARY

• DID NOT OBSERVE IN THESE 22 SUBJECTS RECORDS
  THAT WERE REVIEWED
• OCCURRENCE OF ANY SIGNIFICANT SUICIDE ATTEMPT
  (INCLUDING COMPLETED SUICIDE), OR
• HOSPITALIZATION DUE TO IMMINENT SUICIDE RISK
  (INCLUDING INCREASED LEVEL OF SURVEILLANCE)

8
LIMITATIONS OF INSPECTION

• Subjects did not reveal any events during the
  visits
• Unblinded Psychiatrists did not report any
  events in source documents
• Limited Time and Resources
• Did not follow up discontinued subjects during
  the inspection
• Sampling - approximately 6 (22/368) U.S only