**Clozaril^®^ (clozapine)**

NDA 19-758/S-047

+----------------+-----------------------------------------------------+
| ##### D        | Response to Issue 4 Raised in "Approvable" Letter   |
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| ##### Docum    | Final                                               |
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| #####          | 11-October-2002                                     |
|  Release date: |                                                     |
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| ##### Numbe    | 30                                                  |
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**Available for public disclosure without redaction**

Table of contents

1 Potential Bias in the Referral of Information to the SMB
[3](#potential-bias-in-the-referral-of-information-to-the-smb)

1.1 FDA Issue No. 4: [3](#fda-issue-no.-4)

1.2 Novartis Response to Issue No. 4:
[3](#novartis-response-to-issue-no.-4)

1.2.1 Methods [4](#methods)

1.2.2 Summary of Findings [5](#summary-of-findings)

1.2.3 Conclusion [6](#conclusion)

List of tables

Table 1 Summary of Non-PEP Patients
[5](#table-1-summary-of-non-pep-patients)

Appendix 1: Search Term Dictionary

Appendix 2: Validation of Search Term Dictionary

Appendix 3: Match Profiles for Non-PEP Patients

Appendix 4: Non-PEP Data Review Summary

Appendix 5: Clinical Summary of Non-PEP Patients with a Potential Type 1
Event

# Potential Bias in the Referral of Information to the SMB

## FDA Issue No. 4:

The FDA reviewed data from the Clinical Global Impression of Change in
Severity of Suicidality (CGI-SS) and found that "for both versions of
the CGI-SS, the p-values for the between-treatment contrast using the
ratings of the unblinded investigators were lower (in favor of
clozapine) than those for the between-treatment contrast using the
ratings of the blinded psychiatrist. While clearly not proof of bias in
the unblinded investigators, these findings raise a concern about the
possibility of bias. Furthermore, it is our (FDA) impression that the
vast majority of events reviewed by the SMB were referred to the SMB by
the unblinded investigators. The numbers of referrals and proportions of
those referred who were judged to represent Type 1 events can be
summarized as follows:"

  ----------------- ----------------- ----------------- -----------------
                    **Clozaril**      **Zyprexa**       **Difference**

  Number of         122               157               35
  patients referred                                     
  to SMB                                                

  Number patients   84% (102/122)     90% (141/157)     39
  with a                                                
  SMB-determined                                        
  Type 1 event                                          
  ----------------- ----------------- ----------------- -----------------

"It might be argued that, since the unblinded investigators had primary
responsibility for deciding which events would be forwarded to the SMB,
they may have, due to their bias for clozapine, forwarded more
olanzapine events than clozapine events. Since there is clearly a high
correlation between the number of referrals and the ultimate number of
events judged to be Type 1, any bias in favor of clozapine in deciding
which events to refer might have biased the overall results of this
study in favor of clozapine."

Please fully clarify the source of referrals to the SMB. It is also
critical to describe whether or not the medical monitor was blinded,
and, if not, how this affected the referral rate. Finally, please
provide a listing of the events referred by Ingenix staff to the
unblinded investigators and for which the unblinded investigators
decided not to send them on to the SMB.

## Novartis Response to Issue No. 4:

The protocol required the principal investigator (PI) to assess and
provide documentation concerning clinical events that might be
considered a Type 1 event. To ensure that all potential Type 1 events
were identified and subsequently reviewed by the SMB, the following
procedures contributed to identification of potential Type 1 events (See
Section 3.5.3 of the Clinical Study Report):

1\. During scheduled site visits, the Clinical Research Associates
(CRAs) reviewed source documents for any unreported potential Type 1
events. If any such cases were identified, the CRA informed the Medical
Monitor. The Medical Monitor reviewed these cases and requested the site
to send additional documentation and/or a Potential Endpoint Package
(PEP).

2\. Independently of the CRA site visits, the Medical Monitor reviewed
the Serious Adverse Event Forms. If there was evidence of an unreported
potential Type 1 event, the Medical Monitor asked the site whether the
unreported event might be a potential Type 1 event. Based on the site
response, the Medical Monitor requested via a telephone call or
documented query that a PEP be prepared and submitted to the SMB, unless
the PI provided documentation explicitly noting that this event did not
involve suicidal behavior.

If, following the query, the PI's opinion was that an event was not
related to suicidal behavior then a PEP was not completed. Because the
unblinded PI ultimately decided what constituted suicidal behavior the
potential for bias did exist. To investigate whether such referral bias
was actually present during the study, Novartis performed the following
retrospective review.

### Methods

In the following, "patient" refers to all data in the InterSePT database
for a particular patient.

**Step 1: Identification of Non-PEP Patients**

The database was divided into PEP and non-PEP patients, as it was
assumed that the referral bias would have occurred in the non-PEP
patients (i.e., patients without a potential Type 1 events during the
study).

**Step 2: Review of Non-PEP Patients**

The following databases were used to identify all events potentially
related to suicidal behavior:

1)  Adverse Event (AE) database: Verbatim AE terms from the case report
    form (CRF) AE page.

2)  Query database: Database of documented queries generated during the
    study.

3)  Comments database: Comments of site staff recorded on the CRF
    Comments page.

On the basis of these three databases a search term dictionary was
developed, which included all terms related to suicidal behavior
(Appendix 1). The search term dictionary was embedded in a program that
searched for matches between a dictionary term and the same term in a
particular patient's data. The search term dictionary was validated by
applying the dictionary terms to a random selection of PEP patients
(Appendix 2). All of these PEP patients were successfully identified by
the search program.

The search term dictionary was then applied to all non-PEP patients.
Each search term match yielded the following patient profile (Appendix
3):

-   Patient ID

-   Patient's randomization date

-   Patient's end of study date

-   Retrieved dropout (RDO) index if the patient was a RDO patient

-   Last date of follow-up, if RDO patient

-   AE matches that included PI's AE term, AE start date, AE end date

-   Query matches that included query CRF page, query panel, query text

-   Comment matches that included comment record number, CRF identifier
    of comment, verbatim comment

Appendix 3 contains two types of lists. The first list contains patients
who had at least one match with the AE database, and the second list
contains a patients who did not have an AE match but at least one match
with the Query and/or the Comments database(s).

The CRFs of patients from both lists were reviewed to identify
unreported potential Type 1 events. This review encompassed not only
AEs/SAEs, comments and queries but also all of the relevant clinical
material within the CRF. The review focussed specifically on the
following:

-   Whether or not the PI was queried with respect to the occurrence of
    suicidal behavior

-   If the PI was queried, the PI verbatim response to the query

-   Whether or not the AE was potentially related to suicidal behavior

-   If the AE was potentially related to suicidal behavior, whether or
    not it met the criteria for a PEP

The findings of the review are documented in the "Non-PEP Data Review
Summary" (Appendix 4). Each summary concludes with the Novartis
reviewer's assessment of whether or not the reviewed event met the
criteria for a PEP. If the Novartis reviewer concluded that the event
met the criteria for a PEP, then a Novartis physician reviewed the data
to confirm that the event was a PEP.

### Summary of Findings

There were 701 patients in the study that did not have a PEP. Matches to
at least one term in the search term dictionary occurred in 279 (40%) of
these patients. The review of the data for these 279 non-PEP patients
indicates that 5 (0.01%) of these patients experienced an event that may
have warranted the submission of a PEP to the SMB (Table 1). Clinical
summaries including a Novartis conculsion for these five cases are
provided in Appendix 5.

###### Table 1 Summary of Non-PEP Patients {#table-1-summary-of-non-pep-patients .unnumbered}

  ----------------------------------- -----------------------------------
  **Category**                        **N**

  Total Non-PEP Patients              701

  Total Non-PEP Patients with at      279
  least one match to search term      
  dictionary (Appendicies 3 and 4)    

  Total Non-PEP Patients who          5 (3 Clozaril, 2 Zyprexa)
  experienced an event that may have  
  warranted a PEP (Appendix 5)        
  ----------------------------------- -----------------------------------

### Conclusion

The review of the non-PEP patients shows that, for 3 Clozaril and 2
Zyprexa patients, there were potential Type 1 events that were not
referred to the SMB. On the basis of these findings it appears unlikely
that a bias toward either treatment group existed during the conduct of
InterSePT. The results of this review also suggest that, although the
InterSePT study design did not completely exclude the potential for bias
by the PIs, the PIs themselves acted without bias.

**Appendix 1: Search Term Dictionary**

  ------------------- ---------------------------------------------------
  **Search Terms for  
  Adverse Event       
  Database**          

  **Meddra System     **PI's AE Term**
  Organ Class**       

  **GI disorders**    ABDOMINAL EVENTRATION(SUBSEQUENT TO SUICIDE ATTEMPT
                      PRIOR STUDY START)

                      

  **Injury and        ABRASION LEAFT HAND
  poisoning**         

                      ABRASION ON LEFT-HAND

                      ABRASION ON RIGHT SHIN/ACCIDENT

                      ABRASION ON RIGHT SHIN/ACCIDENTAL

                      ABRASION TO RGT. KNEE

                      ACCIDENTAL FALL

                      ACCIDENTAL OVERDOSE OF STUDY MEDICATION

                      ACCIDENTAL PARIETAL INJURY

                      ACCIDENTAL SUPERFICIAL BURN TO LEFT HAND

                      ACCIDENTLY CUTTING OF HER FEET

                      ACCIDENTLY CUTTING OF HER FEET CRACKED RIBS

                      ALCOHOL BINGE

                      ALCOHOL BINGES

                      ANKLE INJURY-RIGHT (ACCIDENTAL INJURY)

                      BLISTERS LEFT HAND

                      BLISTERS ON FOOT (LEFT)

                      BLISTERS ON HER BACK

                      BROKEN ARM (LEFT) - ACCIDENTAL

                      BROKEN LEG (RIGHT) (ACCIDENTAL)

                      BRUISED RIGHT KNEE (ACCIDENTAL INJURY,DUE TO FALL)

                      BRUISING TO BOTH KNEES (ACCIDENTAL)

                      BURN LEFT MIDDLE FINGER (ACCIDENTAL)

                      BURN ON CALF, ACCIDENTAL

                      BURN TO RIGHT SHOULDER (ACCIDENTAL)

                      COMA DUE TO OVERDOSE (OVERDOSE INTENTIONAL BUT NOT
                      SUICIDE ATTEMPT)

                      CONTUSION ON SCALP - ACCIDENTAL INJURY

                      CRACK COCAINE OVERDOSE (ACCIDENTAL)

                      CUT ON ARM (ACCIDENTAL)

                      CUT ON HEAD (ACCIDENTAL)

                      CUT RIGHT HAND SECONDARY TO ASSAULT

                      DRUG INTOXICATION

                      DRUG TOXICITY

                      DRUNKENNESS

                      ETOA (ALCOHOL) INTOXICATION

                      FRACTURE IN ANKLE (NO ASSOCIATED SUICIDALITY)

                      FRACTURE LEFT FOOT-ACCIDENTAL

                      FRACTURE LEFT WRIST (ACCIDENTALFRACTURE OF LEFT ARM
                      (ACCIDENTAL INJURY)

                      FRACTURE OF LEFT LOWER EXTREMITY-ACCIDENTAL

                      FRACTURE RIGHT ANKLE-ACCIDENTAL

                      FRACTURE RIGHT WRIST-ACCIDENTAL FRACTURED RIGHT ARM

                      FRACTURED SHOULDER

                      FRONTAL INJURY(NOT RELATED TO SUICIDE ATTEMPT)

                      GRAZES TO FOREHEAD (ACCIDENT FOLLOWING OVERDOSE)

                      HAEMATOMA RIGHT HAND (DUE TO VENEPUNCTURE)

                      HAND FRACTURE (ACCIDENTAL)

                      HAND FRACTURE (NOT ASSOCIATED WITH SUICIDE ATTEMPT)

                      HEAD ABRASION-ACCIDENTAL

                      HEAD BRUISE IN PARIETAL REGION (ACCIDENTAL)

                      HEAD INJURY

                      INADVERTENT OVERDOSE

                      INCISION (INJURY OF THE RIGHT HAND BY AN ACCIDENT)

                      INJURED LEFT SHOULDER IN FALL (ACCIDENTAL)

                      INJURED RIGHT ANKLE (ACCIDENTAL)

                      INJURY OF LEFT ARM (ACCIDENTAL)

                      INJURY OF LEFT KNEE (ACCIDENTAL INJURY)

                      INJURY OF LEFT WRIST (ACCIDENTAL INJURY)

                      INTENTIONAL OVERDOSE (NOT SUICIDE ATTEMPT)

                      MINITHIN (OTC DIET AID) OVERDOSE - ACCIDENTAL

                      MORPHINE OVERDOSE, INTENTIONAL (NOT RELATED TO A
                      SUICIDE ATTEMPT)

                      OVERDOSE

                      OVERDOSE (CLEARLY NOT SUICIDE ATTEMPT)

                      OVERDOSE (INTENTIONAL BUT NOT SUICIDE ATTEMPT)
                      (NAI)

                      OVERDOSE (NO ASSOCIATED SUICIDALITY)

                      OVERDOSE (NOT SUICIDE ATTEMPT)

                      OVERDOSE (NOT SUICIDE ATTEMPT,IMPULSIVE AFTER ROW
                      WITH NEIGHBOURS)

                      OVERDOSE (NOT SUICIDE ATTEMPT,NO SPECIFIC AIM)

                      OVERDOSE (NOT SUICIDE ATTEMPT,PSYCHOSOCIAL STRESS)

                      OVERDOSE (RELATED TO ECONOMIC & SOCIAL ISSUES-NO
                      SUICIDE ATTEMPT MADE)

                      SELF HARM (MADE SUPERFICIAL CUTS TO L FOREARM)

                      SELF MUTILATION

                      SELF MUTILATION (PT TRIED TO REMOVE TATTOOS)

                      SLIGHT BURN VESICLES (ACCIDENTAL INJURY)

                      SOFT TISSUE INJURY

                      SUPERFICIAL ABRASION RIGHT HAND (ACCIDENTAL INJURY)

                      SUPERFICIAL ABRASION RIGHT KNEE (ACCIDENTAL INJURY)

                      SUPERFICIAL BURN (ACCIDENTAL)

                      SUPERFICIAL CUT LFT WRIST INTENTIONAL
                      (SELF-MUTILATION) NOT ATTEMPT

                      SUPERFICIAL CUT ON FOREHEAD-ACCIDENT

                      SUPERFICIAL FACIAL SKIN INJURY (ACCIDENTAL)

                      SUPERFICIAL LACERATIONS BILATERAL SHINS-ACCIDENT

                      SUPERFICIAL SCRATCH ON RIGHT HAND-RELATED TO
                      ACCIDENTAL INJURY

                      SUSPECTED OVERDOSE (ACCIDENTAL)

                      UNINTENTIONAL OVERDOSE

                      UNINTENTIONAL OVERDOSE OF 30MG ZYPREXA

                      VERTEBRAL COMPRESSION FRACTURE (ACCIDENTAL)

                      WALKED IN FRONT OF CAR (ACCIDENTAL

                      WOUND IN FOREARM(RIGHT) (NOT SUICIDE ATTEMPT)

                      

  **Psychiatric       (PRUSIONISM) SELF MUTILATION
  disorders**         

                      BRUISE RIGHT HAND (ACCIDENTAL INJURY)

                      BRUISE TO FOREHEAD (ACCIDENTAL INJURY)

                      BRUISE TO L HAND (ACCIDENTAL

                      BRUISED ANKLE

                      BRUISED BOTH ARMS

                      BRUISED EYE (DUE TO ACCIDENTAL FALL)

                      BRUISED LEFT EYE

                      BRUISED RIBS

                      BRUISES (BOTH ARMS ACCIDENTAL)

                      BRUISING TO RIGHT ELBOW

                      DEATH BY SUICIDE(HANGING

                      DESIRE TO SELF-HARM

                      DESTRUCTIVE BEHAVIOR

                      EXPRESSING SUICIDE IDEAS

                      FEELING SUICIDAL

                      FELT SUICIDAL

                      FRACTURE OF RIGHT TIBIA AND FIBULA (SUICIDE
                      ATTEMPT)

                      HOSPITAL ADMISSION DUE TO STRESS

                      HOSPITALISATION DUE TO INCREASING OF SCHIZOPHRENIA

                      HOSPITALISATION DUE TO MEDICATION CHANGE DUE TO
                      DEPRESSION

                      HOSPITALISATION FOR ANXIETY

                      HOSPITALISATION FOR THERAPY TITRATION DUE TO
                      SUICIDAL IDEATION

                      HOSPITALIZATION DUE TO INCREASING PSYCHOSIS

                      HOSPITALIZATION DUE TO PREVENTION OF HETROAGRESIVE
                      BEHAVIOR.

                      HOSPITALIZATION TO PREVENT SUICIDE ATTEMPT

                      HOSPITALIZED - SUICIDAL IDEATION

                      IMMINENT RISK OF SUICIDE

                      INCREASE IN SUICIDAL IDEATION

                      INCREASE IN SUICIDAL IDEATIONS

                      INCREASE IN SUICIDALITY

                      INCREASE OF SUICIDAL IDEATION

                      INCREASE OF SUICIDAL IDEATIONS

                      INCREASE OF SUICIDALITY

                      INCREASE OF SUICIDALITY,SUICIDAL THOUGHTS

                      INCREASE OF SURVEILLANCE (BECAUSE PATIENT OVERDOSED
                      ON ZOPICLONE)

                      INCREASE SUICIDAL IDEATION

                      INCREASE SUICIDALITY

                      INCREASE SUICIDALITY HOSPITALIZATION

                      INCREASED RISK OF SUICIDE

                      INCREASED RISK OF SUICIDE ATTEMPT

                      INCREASED SELF-HARM BEHAVIOR

                      INCREASED SUCIDALITY

                      INCREASED SUICIDAL IDEATION

                      INCREASED SUICIDAL IDEATIONS

                      INCREASED SUICIDAL THOUGHTS

                      INCREASED SUICIDALITY

                      INCREASED THOUGHTS OF SELF HARM

                      INJURY OF LEFT WRIST (RELATED TO SUICIDE ATTEMPT)

                      INJURY PAIN (DUE TO CUT ON LEFT LOWER ARM FROM
                      SUICIDE ATTEMPT

                      INTENTIONAL LACERATED RIGHT FOREARM-NOT RELATED TO
                      SUICIDE ATTEMPT

                      INTENTIONAL SUPERFICIAL CUT ON FOREARM RELATED TO
                      SUICIDE ATTEMPT

                      INTERMITTENT SUICIDAL IDEATION

                      INTERMITTENT SUICIDAL IDEATIONS

                      MILD SUICIDAL IDEATION

                      MILDLY SUICIDAL

                      OVERDOSE (SUICIDE ATTEMPT)

                      OVERDOSE OF CON-MEDS (SUICIDE ATTEMPT)

                      OVERDOSE/SUICIDE ATTEMPT

                      OVERDOSE-INTENTIONAL-GESTURE

                      OVERDOSE-SUICIDE ATTEMPT

                      RIGHT FOOT METATARSUS FRACTURE (RELATED TO SUICIDE
                      ATTEMPT)

                      RISK OF SELF HARM

                      SCRATCHES-LEFT FOREARM AND LEFT LEG
                      (SELF-INFLICTED)

                      SELF HARM (CUT LEFT FOREARM)(GESTURE NOT SUICIDE
                      ATTEMPT)

                      SELF INFLICTED BURNS LEFT HAND-NOT RELATED TO
                      SUICIDE ATTEMPT

                      SELF INFLICTED CUT TO LEFT ARM-NOT RELATED TO
                      SUICIDE ATTEMPT

                      SELF INFLICTED SCRATCHES TO LEFT ARM -NOT RELATED
                      TO SUICIDE ATTEMPT

                      SELF MUTILATION DELUSION

                      SELF-HARM (IDEAS OF)

                      SELF-HARM IDEATION

                      SELF-HARM SUPERFICIAL LACERATIONS TO RIGHT FOOT
                      (NOT SUICIDE ATTEMPT)

                      SELF-INDUCED VOMITING

                      SELF-MUTILATION

                      SEVERELY SUICIDAL

                      SUCIDAL IDEATION

                      SUICICDAL IDEATION

                      SUICIDAL

                      SUICIDAL ATTEMPT - HANGING

                      SUICIDAL ATTEMPT (OVERDOSE AND SWALLOWING A PIECE
                      OF SOAP)

                      SUICIDAL ATTEMPT BY JUMPING

                      SUICIDAL ATTEMPT BY OVERDOSE

                      SUICIDAL ATTEMPT/DRUG

                      SUICIDAL ATTEMPT/OVERDOSE

                      SUICIDAL GESTURE(MILD OVERDOSE)

                      SUICIDAL IDEALISM

                      SUICIDAL IDEAS

                      SUICIDAL IDEATION

                      SUICIDAL IDEATION AND PLAN

                      SUICIDAL IDEATION INCREASE

                      SUICIDAL IDEATION INCREASED

                      SUICIDAL IDEATION SECONDARY TO CHRONIC BACK PAIN

                      SUICIDAL IDEATION SECONDARY TO LEG PAIN AND
                      HERNIATED DISC

                      SUICIDAL IDEATION W/PLAN

                      SUICIDAL IDEATION(VAGUE)

                      SUICIDAL IDEATION/SUICIDE ATTEMPT

                      SUICIDAL IDEATION-INTERMITTENT

                      SUICIDAL IDEATION-PASSIVE

                      SUICIDAL IDEATIONS

                      SUICIDAL INTENTION

                      SUICIDAL THINKING

                      SUICIDAL THINKING WITH IMMINENT RISK OF SUICIDE

                      SUICIDAL THOUGHT

                      SUICIDAL THOUGHTS

                      SUICIDAL THOUGHTS (INTERMITTENT)

                      SUICIDAL THOUGHTS (SUICIDAL RISK)

                      SUICIDAL THREATS

                      SUICIDALITY

                      SUICIDALITY (SUBSEQUENT HOSPITAL ADMISSION)

                      SUICIDALITY(WORSENING)

                      SUICIDE

                      SUICIDE (JUMPING IN FRONT OF A TRAIN)-DEATH

                      SUICIDE ATTEMPT

                      SUICIDE ATTEMPT - OVERDOSE

                      SUICIDE ATTEMPT (BLEACHED RIGHT AND LEFT EYES)

                      SUICIDE ATTEMPT (CARBON MONOXIDE POISONING)

                      SUICIDE ATTEMPT (CUTTING OF LEFT FOREARM)

                      SUICIDE ATTEMPT (DUE TO ZYPREXA OVERDOSE)

                      SUICIDE ATTEMPT (ELECTRICITY)

                      SUICIDE ATTEMPT (HANGING)

                      SUICIDE ATTEMPT (HANGING+PHLEBOTOMY)

                      SUICIDE ATTEMPT (JUMPED IN A RIVER)

                      SUICIDE ATTEMPT (JUMPED IN FRONT OF MOVING VEHICLE)

                      SUICIDE ATTEMPT (OVERDOSE OF HEROIN)

                      SUICIDE ATTEMPT (OVERDOSE OF RIVOTRIL)

                      SUICIDE ATTEMPT (OVERDOSE)

                      SUICIDE ATTEMPT (PATIENT STOOD ON BRIDGE)

                      SUICIDE ATTEMPT (RAN ALONG CROWDED AVENUE-INTENTION
                      OF BEING KILLED)

                      SUICIDE ATTEMPT (RUSSIAN ROULETTE WITH GUN)

                      SUICIDE ATTEMPT (SELF INFLICTED LACERATIONS TO
                      RIGHT WRIST WITH BLADE)

                      SUICIDE ATTEMPT (SLASHING OF LEFT ARM)

                      SUICIDE ATTEMPT (TRAFFIC ACCIDENT)

                      SUICIDE ATTEMPT (WALKED INTO TRAFFIC WITH EYES
                      CLOSED)

                      SUICIDE ATTEMPT (WENT INTO A LAKE)

                      SUICIDE ATTEMPT (WRIST SLASHING)

                      SUICIDE ATTEMPT (WRIST SLASHING,SELF MUTILATION)

                      SUICIDE ATTEMPT BY ACUTE POLYPHARMACY INTOXICATION
                      RESULTING IN DEATH

                      SUICIDE ATTEMPT BY ASPHYXIATION

                      SUICIDE ATTEMPT BY BURNING LEADING TO DEATH

                      SUICIDE ATTEMPT BY HANGING

                      SUICIDE ATTEMPT BY HANGING RESULTING IN DEATH

                      SUICIDE ATTEMPT BY INGESTION OF LAMP OIL

                      SUICIDE ATTEMPT BY INGESTION OF POISON

                      SUICIDE ATTEMPT BY LACERATION

                      SUICIDE ATTEMPT BY O.D.

                      SUICIDE ATTEMPT BY OVERDOSE

                      SUICIDE ATTEMPT BY OVERDOSE (DUE TO INCR.
                      PSYCHOSIS,LIFE STRESS EVENT)

                      SUICIDE ATTEMPT BY OVERDOSE (WITH PARACETAMOL
                      (INTENTIONAL))

                      SUICIDE ATTEMPT BY OVERDOSE ATTEMPT

                      SUICIDE ATTEMPT BY OVERDOSE LEADING TO DEATH

                      SUICIDE ATTEMPT BY OVERDOSE(GESTURE SEEKING)

                      SUICIDE ATTEMPT BY POISONING BY KITCHENS GAS

                      SUICIDE ATTEMPT BY SELF-MUTILATION

                      SUICIDE ATTEMPT DUE TO PSYCHOSIS(SELFMUTILATION-PT
                      CUT LEFT LOWER ARM)

                      SUICIDE ATTEMPT VIA WRIST SLASHING

                      SUICIDE ATTEMPT WITH OVERDOSE

                      SUICIDE ATTEMPT, SELF-MUTILATION

                      SUICIDE ATTEMPT/HANGING/DEATH

                      SUICIDE ATTEMPT/INCREASE PSYCHOSIS

                      SUICIDE ATTEMPT/OVERDOSE

                      SUICIDE ATTEMPT/SELF HARM

                      SUICIDE ATTEMPT-CUT WRIST WITH PAPER CLIP

                      SUICIDE ATTEMPT-GESTURES

                      SUICIDE ATTEMPT-HEAD BANGING

                      SUICIDE ATTEMPT-LACERATIONS TO WRISTS

                      SUICIDE ATTEMPT-OVERDOSE

                      SUICIDE ATTEMPT-OVERDOSE OF RESTORIL

                      SUICIDE ATTEMPT-OVERDOSE OF TRIAL AND CONCOMITANT
                      MEDICATION

                      SUICIDE GESTURE

                      SUICIDE IDEATION

                      SUICIDE INTENTIONS

                      SUICIDE RISK

                      SUICIDE THREAT

                      SUICIDE/DEATH BY HANGING

                      SUPERFICIAL ABRASIONS LEFT FOREARM(INTENTIONAL)

                      SUPERFICIAL ABRASIONS LEFT WRIST (INTENTIONAL)

                      SUPERFICIAL ABRASIONS RIGHT FOREARM (INTENTIONAL)

                      SUPERFICIAL CUT TO LEFT FOREARM (GESTURE)

                      SUPERFICIAL CUTS-LEFT FOREARM (SELF-INFLICTED)

                      SUPERFICIAL LACERATIONS TO WRISTS (TO FEEL PAIN,
                      NOT TO KILL HERSELF)

                      SUPERFICIAL LACERATIONS TO WRISTS(TO EXPERIENCE
                      PAIN,NOT ATTEMPT)

                      SUPERFICIAL SCRATCHES-BOTH FOREARMS SELF-INFLICTED
                      NOT SUICIDE ATTEMPT

                      THOUGHTS OF OVERDOSING

                      THOUGHTS OF SELF HARM

                      THOUGHTS OF SELF-HARM (PATIENT DID NOT MAKE SUICIDE
                      ATTEMPT)

                      THOUGHTS OF SELF-HARM WITH SUICIDAL IDEATION

                      THREAT OF FIRE SETTING

                      THREATENING TO OVERDOSE

                      WORSENING OF SUICIDALITY

                      ZYPREXA OVERDOSE -- INTENTIONAL

                      

  **Social            ADMISSION FOR OBSERVATION (FOR POSSIBLE REBOUND
  Circumstances**     PSYCHOSIS)

                      ADMISSION FOR RESPITE CARE

                      ADMISSION FOR RESPITE CARE IN RESIDENTIAL HOME

                      ADMISSION FOR SOCIAL REASON

                      HOSP DUE TO FAMILY CONFLICT

                      HOSPITAL ADMISSION(RESPITE CARE)

                      HOSPITALISATION DUE TO FAMILY CONFLICT

                      HOSPITALISATION DUE TO SOCIAL REASON

                      HOSPITALISATION DUE TO SOCIAL REASONS

                      HOSPITALISATION FOR LONELINESS

                      HOSPITALISATION FOR SOCIAL REASON

                      HOSPITALISATION FOR SOCIAL REASONS

                      HOSPITALISATION FOR SOCIAL REASONS (PSYCHOSIS)

                      HOSPITALIZATION DUE TO ASSESSMENT TO WORKING
                      ABILITY

                      HOSPITALIZATION DUE TO SOCIAL REASONS

                      HOSPITALIZATION FOR SOCIAL REASON

                      HOSPITALIZATION FOR SOCIAL REASONS

                      

  **Surgical and      BRUISING OVER R ANTECUBITAL FOSSA (ACCIDENTAL AND
  Medical             DUE TO VENEPUNCTURE)
  Procedures**        

                      BRUISING OVER RIGHT ANTECUBITAL FOSSA-ACCIDENTAL
                      DUE TO VENIPUNCTURE

                      HOSPITALIZATION FOR BETTER SURVEILLANCE OF THE
                      COMPLIANCE OF STUDY MED

                      HOSPITALIZATION FOR PRACTICAL REASONS

  **Search Terms for  
  Query and CRF       
  Comments            
  Databases**         

  **Search Term**     HIGHER LEVEL OF SURVEILLANCE FOR SUICIDALITY

                      PE

                      PEP

                      POTENTIAL ENDPOINT

                      SUICIDE ATTEMPT

                      TYPE 1
  ------------------- ---------------------------------------------------

**Appendix 2: Validation of Search Term Dictionary**

Novartis PEP Patients For Search Term Review Protocol ABA451

Search Matches for ABA-451-106-0010 (Randomization: 15OCT1998, EOS:
09FEB2001)

AE term AE Dates

\-\-\-\-\-\-\-\-\-\-\--SUICIDAL IDEATION 09/06/2000 to
09/08/2000\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDALITY 01/03/1999 to
01/05/1999\-\-\-\-\-\-\-\-\-\-\--

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Query matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Comment matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[/proj/genesis/data/devl/CLEX123/CLEX123ABA451/final/pgm_eff/srchchku.sas\]
Table Generation: 10OCT02

Novartis PEP Patients For Search Term Review Protocol ABA451

Search Matches for ABA-451-114-0002 (Randomization: 16JUL1998, EOS:
08SEP1998)

AE term AE Dates

\-\-\-\-\-\-\-\-\-\-\--SUICIDAL IDEATION 08/07/1998 to
08/12/1998\-\-\-\-\-\-\-\-\-\-\--

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Query matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Comment matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[/proj/genesis/data/devl/CLEX123/CLEX123ABA451/final/pgm_eff/srchchku.sas\]
Table Generation: 10OCT02

Novartis PEP Patients For Search Term Review Protocol ABA451

Search Matches for ABA-451-123-0002 (Randomization: 12AUG1998, EOS:
08DEC1999, RDO Patient, RDO Last Date: 23AUG2000)

AE term AE Dates

\-\-\-\-\-\-\-\-\-\-\--SUICIDALITY 12/10/1999 to
12/20/1999\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDALITY 08/30/1998 to
09/17/1998\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDE ATTEMPT (OVERDOSE) 11/24/1999 to
11/24/1999\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDE ATTEMPT (OVERDOSE) 03/25/1999 to
03/26/1999\-\-\-\-\-\-\-\-\-\-\--

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Query matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Matched Comment

Rec \# CRF Identifier Comment

4 DC (SUICIDE ATTEMPT). PLEASE NOTE THAT PT

HAD EXTRA MEDICATION FROM

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[/proj/genesis/data/devl/CLEX123/CLEX123ABA451/final/pgm_eff/srchchku.sas\]
Table Generation: 10OCT02

Novartis PEP Patients For Search Term Review Protocol ABA451

Search Matches for ABA-451-123-0007 (Randomization: 21AUG1998, EOS:
10NOV1998, RDO Patient, RDO Last Date: 04AUG1999)

AE term AE Dates

\-\-\-\-\-\-\-\-\-\-\--SUICIDALITY 10/01/1998 to
10/22/1998\-\-\-\-\-\-\-\-\-\-\--

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Query matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Comment matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[/proj/genesis/data/devl/CLEX123/CLEX123ABA451/final/pgm_eff/srchchku.sas\]
Table Generation: 10OCT02

Novartis PEP Patients For Search Term Review Protocol ABA451

Search Matches for ABA-451-125-0018 (Randomization: 27OCT1998, EOS:
23OCT2000)

AE term AE Dates

\-\-\-\-\-\-\-\-\-\-\--SUICIDAL IDEATION 03/11/1999 to
03/19/1999\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDALITY 12/28/1998 to
01/22/1999\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDALITY 12/08/1998 to
12/10/1998\-\-\-\-\-\-\-\-\-\-\--

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Query matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Comment matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[/proj/genesis/data/devl/CLEX123/CLEX123ABA451/final/pgm_eff/srchchku.sas\]
Table Generation: 10OCT02

Novartis PEP Patients For Search Term Review Protocol ABA451

Search Matches for ABA-451-304-0011 (Randomization: 12JAN1999, EOS:
09JAN2001)

AE term AE Dates

\-\-\-\-\-\-\-\-\-\-\--BRUISED BOTH ARMS 04/26/2000 to
05/09/2000\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--BRUISED LEFT EYE 04/26/2000 to
05/09/2000\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--FEELING SUICIDAL 02/10/1999 to
02/22/1999\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--FEELING SUICIDAL 01/31/1999 to
02/09/1999\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDAL IDEATION 10/09/1999 to
11/16/1999\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDAL IDEATION 04/25/2000 to
05/04/2000\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDALITY (SUBSEQUENT HOSPITAL ADMISSION)
06/06/2000 to 07/24/2000\-\-\-\-\-\-\-\-\-\-\--

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Query matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Comment matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[/proj/genesis/data/devl/CLEX123/CLEX123ABA451/final/pgm_eff/srchchku.sas\]
Table Generation: 10OCT02

Novartis PEP Patients For Search Term Review Protocol ABA451

Search Matches for ABA-451-401-0003 (Randomization: 20AUG1998, EOS:
17AUG2000)

AE term AE Dates

\-\-\-\-\-\-\-\-\-\-\--INCREASE OF SUICIDAL IDEATION 05/07/1999 to
06/07/1999\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--INCREASE OF SUICIDALITY 10/13/1999 to EOS
\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDAL IDEATION 04/16/1999 to
05/07/1999\-\-\-\-\-\-\-\-\-\-\--

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Query matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Comment matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[/proj/genesis/data/devl/CLEX123/CLEX123ABA451/final/pgm_eff/srchchku.sas\]
Table Generation: 10OCT02

Novartis PEP Patients For Search Term Review Protocol ABA451

Search Matches for ABA-451-605-0006 (Randomization: 25AUG1998, EOS:
21AUG2000)

AE term AE Dates

\-\-\-\-\-\-\-\-\-\-\--INCREASED RISK OF SUICIDE ATTEMPT 09/23/1998 to
11/02/1998\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDAL IDEATION 05/05/1999 to
06/14/1999\-\-\-\-\-\-\-\-\-\-\--

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Query matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Matched Comment

Rec \# CRF Identifier Comment

2 BK 6050006 THE PATIENT TOLD US,SHE HAD SUICIDE

ATTEMPT WHEN SHE WAS 14 YEARS

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[/proj/genesis/data/devl/CLEX123/CLEX123ABA451/final/pgm_eff/srchchku.sas\]
Table Generation: 10OCT02

Novartis PEP Patients For Search Term Review Protocol ABA451

Search Matches for ABA-451-903-0005 (Randomization: 10DEC1998, EOS:
03MAY1999, RDO Patient, RDO Last Date: 04DEC2000)

AE term AE Dates

\-\-\-\-\-\-\-\-\-\-\--SUICIDE ATTEMPT (OVERDOSE) 01/06/1999 to
01/07/1999\-\-\-\-\-\-\-\-\-\-\--

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Query matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Matched Comment

Rec \# CRF Identifier Comment

3 BK1 NUMBER OF LIFETIME SUICIDE ATTEMPTS(2

DOCUMENTED)7 IS THE BEST GUESS

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[/proj/genesis/data/devl/CLEX123/CLEX123ABA451/final/pgm_eff/srchchku.sas\]
Table Generation: 10OCT02

Novartis PEP Patients For Search Term Review Protocol ABA451

Search Matches for ABA-451-956-0003 (Randomization: 23DEC1998, EOS:
19DEC2000)

AE term AE Dates

\-\-\-\-\-\-\-\-\-\-\--SUICIDAL IDEATION 09/14/1999 to
11/04/1999\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDE ATTEMPT BY INGESTION OF POISON 12/26/1998
to 12/26/1998\-\-\-\-\-\-\-\-\-\-\--

\-\-\-\-\-\-\-\-\-\-\--SUICIDE RISK 01/05/1999 to
01/15/1999\-\-\-\-\-\-\-\-\-\-\--

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

This patient has no Query matches.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Matched Comment

Rec \# CRF Identifier Comment

1 DC PATIENT DIDNT TAKE ZYPREXA FOR SEVERAL

DAYS DUE TO HIS SUICIDE ATTEMPT

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[/proj/genesis/data/devl/CLEX123/CLEX123ABA451/final/pgm_eff/srchchku.sas\]
Table Generation: 10OCT02

List of PEPs for Selected Patients

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Did SMB

consider

Patient ID Event Date endpt? Which type of endpt?

\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\-\--

ABA-451-106-0010 01/03/1999 No .

09/06/2000 No .

ABA-451-114-0002 08/07/1998 Yes Hosp.risk suicide/incr.lvl.surv

ABA-451-123-0002 03/25/1999 Yes Suicide attempt

04/10/2000 Yes Hosp.risk suicide/incr.lvl.surv

08/30/1998 Yes Hosp.risk suicide/incr.lvl.surv

11/24/1999 No .

12/10/1999 Yes Hosp.risk suicide/incr.lvl.surv

ABA-451-123-0007 01/13/1999 Yes Hosp.risk suicide/incr.lvl.surv

04/26/1999 Yes Hosp.risk suicide/incr.lvl.surv

10/01/1998 Yes Hosp.risk suicide/incr.lvl.surv

ABA-451-125-0018 03/11/1999 Yes Hosp.risk suicide/incr.lvl.surv

12/31/1998 Yes Hosp.risk suicide/incr.lvl.surv

ABA-451-304-0011 01/31/1999 Yes Hosp.risk suicide/incr.lvl.surv

06/06/2000 Yes Hosp.risk suicide/incr.lvl.surv

ABA-451-401-0003 05/07/1999 Yes Hosp.risk suicide/incr.lvl.surv

ABA-451-605-0006 05/19/1999 Yes Hosp.risk suicide/incr.lvl.surv

09/23/1998 Yes Hosp.risk suicide/incr.lvl.surv

ABA-451-903-0005 01/06/1999 Yes Suicide attempt

ABA-451-956-0003 01/05/1999 Yes Hosp.risk suicide/incr.lvl.surv

10/20/1999 Yes Hosp.risk suicide/incr.lvl.surv

12/26/1998 Yes Suicide attempt

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

\[/proj/genesis/data/devl/CLEX123/CLEX123ABA451/final/pgm_eff/srchchku.sas\]
Table Generatio n: 10OCT02

**Appendix 3: Match Profiles for Non-PEP Patients**

**Appendix 4: Non-PEP Data Review Summary**

**Appendix 5: Summary of Non-PEP Patients**

**1. Patient 604-0022: Suicidal Ideation, December 6, 1998 (Clozaril)**

This patient was randomized to Clozaril on Dec. 3, 1998 and 3 days later
(Dec. 6, 1998) was hospitalized with the diagnosis of " Hospitalization
due to psychosis".

The SAE report states that the patient's psychotic symptoms were not
increased compared to baseline. The psychotic symptoms were also
combined with depression and suicidal statement.

She was known for vagabond lifestyle. The dose of Clozaril was increased
in order to avoid further "sauntering" and losing the patient.

PI was queried and respond on 20/01/00 confirmed that psychotic symptoms
had not increased but that patient was hospitalized due to accompanying
depression and suicidal ideation/statement. The rating scales from 2
days earlier (baseline) were:

CGI SS PI/BP-3(moderately suicidal)

CGI SP- 5 (markedly psychotic)

ISST PI/BP- wish to die-2 (moderately strong)

Living/vs dying-2(dying outweigh for living)

Desire to make suicidal attemt-2 (moderately strong)

Passive suicidal desire-2 (would avoid steps necessary to save or
maintain life)

Frequency of suicidal ideation-2(persistent or continuous)

CDS hopelessness - 3 (severe), the rest of the ratings are 2(moderate)

Medical monitor queried the PI and reported: "Investigator confirmed
that hospitalization was due to psychosis. The patient was hospitalized
to ensure the proper level of psychiatric care and to prevent early
discontinuation. No life treating condition occurred".

Conclusion: Taking into consideration the time of the event (3 days
after randomization), the rating scales at baseline (2 days prior the
event) and the confirmation from the investigator (see above) this event
did not meet PEP criteria.

**2. Patient 404-0008 Suicidal Ideation, November 13, 1999 (Clozaril)**

Patient was hospitalized prior to the start of study18 Jan. 98 and
discharged after the study end (3 January 2000).

The suicidal ideation was marked "severe" (same at baseline on CDS), but
did not meet the definition of "serious". No action taken-was reported.
There is no rescue intervention form filled out for this event.

On November 18, 1999 (3 days after the AE start date):

CGI-SS PI and BP 4-severely suicidal (baseline rating reported 3-
moderately suicidal),

suicidality changed compared to baseline - 6 (much worse).

PI was not queried.

Conclusion: A PEP should have been completed and submitted.

**3. Patient 303-0010: Suicide attempt by burning leading to death,**

**October 10 , 2000 (Clozaril)**

Occurred 4 days after the study completion (2 years and 4 days).

Conclusion: This event did not meet PEP criteria.

**4. Patient 955-0014: Increase in suicidality, March 3, 1999
(Zyprexa)**

Patient was hospitalized for increase in psychosis but SAE report
specified that patient was not able to control his psychotic symptoms;
subtle increase in suicidality and sentiments of hopelessness.

PI was queried and agreed on AE of Increase in suicidality.

The event was marked as follows:

seriousness- serious,

severity-severe,

action taken-hospitalization, concomitant medication.

Conclusion: A PEP should have been completed and submitted.

**5. Patient 604-0029: Overdose, June 19,1999 (Zyprexa)**

The PI clarified in the SAE report that the overdose was not a suicidal
attempt. The patient wanted to treat her psychotic symptoms with a
higher dose of a prescribed anxiolytic.

Conclusion: This event did not meet PEP criteria.