**REVIEW AND EVALUATION OF CLINICAL DATA**

  ---------------------------------- ------------------------------------
  **Application Information**        

  NDA#:                              19-758/S-047

  Sponsor:                           Novartis

  Due Date:                          September 1, 2002

  **Drug Name:**                     

  Generic Name:                      Clozapine

  Trade Name:                        Clozaril

  **Drug Categorization:**           

  Pharmacological Class:             D~4~/5-HT receptor antagonist

  Proposed Indication:               Suicidality

  Dosage Forms:                      25mg and 100mg tablets

  Route:                             Oral

  **Review Information**             

  Clinical Reviewer:                 Gregory M. Dubitsky, M.D.

  Completion Date:                   August 1, 2002
  ---------------------------------- ------------------------------------

+-------------------------------------------------------------+--------+
| **NDA 19-758/S-047**                                        |        |
|                                                             |        |
| **clozaril for suicidality**                                |        |
|                                                             |        |
| **table of contents**                                       |        |
+-------------------------------------------------------------+--------+
| **Section**                                                 | **     |
|                                                             | Page** |
+-------------------------------------------------------------+--------+
| **EXECUTIVE SUMMARY**                                       |        |
+-------------------------------------------------------------+--------+
| I. Recommendations                                          |        |
+-------------------------------------------------------------+--------+
| > A. Recommendation on Approvability                        | 4      |
+-------------------------------------------------------------+--------+
| > B. Recommendation for Phase 4 Studies                     | 4      |
+-------------------------------------------------------------+--------+
| II\. Summary of Clinical Findings                           |        |
+-------------------------------------------------------------+--------+
| > A. Brief Overview of Clinical Program                     | 4      |
+-------------------------------------------------------------+--------+
| > B. Efficacy                                               | 4      |
+-------------------------------------------------------------+--------+
| > C. Safety                                                 | 5      |
+-------------------------------------------------------------+--------+
|                                                             |        |
+-------------------------------------------------------------+--------+
| **CLINICAL REVIEW**                                         |        |
+-------------------------------------------------------------+--------+
| I. Introduction and Background                              |        |
+-------------------------------------------------------------+--------+
| > A. Role in the Treatment Armamentarium                    | 5      |
+-------------------------------------------------------------+--------+
| > B. Administrative History                                 | 5      |
+-------------------------------------------------------------+--------+
| > C. Proposed Instructions for Use                          | 9      |
+-------------------------------------------------------------+--------+
| II\. Clinically Relevant Findings from Consultant Reviews   |        |
+-------------------------------------------------------------+--------+
| A. Statistical Review and Evaluation                        | 9      |
+-------------------------------------------------------------+--------+
| B. DSI Clinical Site Inspections                            | 9      |
+-------------------------------------------------------------+--------+
| III\. Human Pharmacokinetics and Pharmacodynamics           | 9      |
+-------------------------------------------------------------+--------+
| IV\. NDA Data Sources                                       |        |
+-------------------------------------------------------------+--------+
| > A. Study ABA 451                                          | 10     |
+-------------------------------------------------------------+--------+
| > B. Published Literature                                   | 11     |
+-------------------------------------------------------------+--------+
| V. Clinical Review Methods                                  |        |
+-------------------------------------------------------------+--------+
| > A. Items Utilized in the Review                           | 11     |
+-------------------------------------------------------------+--------+
| > B. Methods Used to Evaluate Data Quality                  | 12     |
+-------------------------------------------------------------+--------+
| > C. Adherence to Accepted Ethical Standards                | 12     |
+-------------------------------------------------------------+--------+
| > D. Evaluation of Financial Disclosure                     | 12     |
+-------------------------------------------------------------+--------+
| VI\. Integrated Review of Efficacy                          |        |
+-------------------------------------------------------------+--------+
| > A. Overview of Data Relevant to Efficacy                  | 14     |
+-------------------------------------------------------------+--------+
| > B. Study ABA 451                                          | 14     |
+-------------------------------------------------------------+--------+
| > C. Important Clinical Issues Pertinent to Efficacy        |        |
+-------------------------------------------------------------+--------+
| > 1\. Suicidality Indication                                | 31     |
+-------------------------------------------------------------+--------+
| > 2\. Predictors of Response                                | 33     |
+-------------------------------------------------------------+--------+
| > 3\. Size of Treatment Effect                              | 35     |
+-------------------------------------------------------------+--------+
| > 4\. Choice of Dose                                        | 36     |
+-------------------------------------------------------------+--------+
| > 5\. Duration of Treatment                                 | 36     |
+-------------------------------------------------------------+--------+
| > D. Summary of Pertinent Published Literature              | 36     |
+-------------------------------------------------------------+--------+
| > E. Assessment of Efficacy Data Quality                    | 43     |
+-------------------------------------------------------------+--------+
| > F. Conclusions Regarding Efficacy                         | 45     |
+-------------------------------------------------------------+--------+
| VII\. Integrated Review of Safety                           |        |
+-------------------------------------------------------------+--------+
| A. Methodology of the Safety Review                         | 45     |
+-------------------------------------------------------------+--------+
| B. Safety Findings                                          | 46     |
+-------------------------------------------------------------+--------+
| 1\. Deaths                                                  | 46     |
+-------------------------------------------------------------+--------+
| 2\. All Serious Adverse Events                              | 46     |
+-------------------------------------------------------------+--------+
| 3\. Dropouts due to Adverse Events                          | 47     |
+-------------------------------------------------------------+--------+
| C. Adequacy of Exposure & Safety Assessments                | 48     |
+-------------------------------------------------------------+--------+
| D. Safety Data Quality & Completeness                       | 48     |
+-------------------------------------------------------------+--------+
| E. Summary of Important Safety Findings                     |        |
+-------------------------------------------------------------+--------+
| 1\. WBC Count Decreased                                     | 49     |
+-------------------------------------------------------------+--------+
| 2\. Bowel Obstruction                                       | 49     |
+-------------------------------------------------------------+--------+
| 3\. Hyperglycemia                                           | 50     |
+-------------------------------------------------------------+--------+
| 4\. Dizziness                                               | 51     |
+-------------------------------------------------------------+--------+
| 5\. Somnolence                                              | 51     |
+-------------------------------------------------------------+--------+
| F. Safety Conclusions                                       | 51     |
+-------------------------------------------------------------+--------+
| VIII\. Dosing, Regimen, and Administrative Issues           | 52     |
+-------------------------------------------------------------+--------+
| IX\. Use in Special Populations                             | 52     |
+-------------------------------------------------------------+--------+
| X. Review of Proposed Labeling                              | 52     |
+-------------------------------------------------------------+--------+
| XI\. Conclusions and Recommendations                        | 52     |
+-------------------------------------------------------------+--------+
| XII\. Appendices                                            | 55     |
+-------------------------------------------------------------+--------+

**EXECUTIVE SUMMARY**

**I. Recommendations**

**A. Recommendation on Approvability**

The sponsor is requesting an indication for the use of Clozaril in the
treatment of suicidality in patients with schizophrenia and
schizoaffective disorder. It is recommended that this indication not be
approved.

**B. Recommendations for Phase 4 Studies**

At this time, there are no recommendations for Phase 4 studies.

**II. Summary of Clinical Findings**

**A. Brief Overview of the Clinical Program**

Support for the requested indication derives solely from one clinical
trial, study ABA 451. This was a multicenter, randomized, open-label
comparison of Clozaril and Zyprexa with respect to suicidality risk over
a treatment period of 2 years in 980 patients with schizophrenia or
schizoaffective disorder. Raters of suicidality outcome measures were to
be blinded to the patient's treatment.

**B. Efficacy**

On face, study ABA 451 provides evidence to suggest a reduced risk of
suicidality over two years among patients treated with Clozaril versus
Zyprexa. However, there were a number of irregularities in the conduct
and analysis of this study that preclude a definitive interpretation of
the study results at this time. These problems are further discussed in
section VI.B.12 below.

Moreover, the indication sought by the sponsor, treatment of
suicidality, is distinctly different from the indication which may be
supported by ABA 451, a reduction in suicide risk with long-term
therapy. This issue is discussed in more detail in section VI.C.1 below.

**C. Safety**

A limited review of the safety data from study ABA 451 revealed a number
of clinically significant adverse experiences associated with Clozaril:
white blood cell count decreases, bowel obstruction, hyperglycemia,
non-vertiginous dizziness, and somnolence.

None of these represented previously unrecognized toxicities which would
preclude the approval of this supplement or require amendment of
Clozaril labeling.

**CLINICAL REVIEW**

**I. Introduction and Background**

**A. Role in the Treatment Armamentarium**

Suicide is an important contributor to the shorter life expectancy among
patients with schizophrenia compared to the general population. It has
been estimated that approximately 10% of patients with schizophrenia
commit suicide; this fraction may be even higher in patients with
treatment-refractory schizophrenia. Risk factors for suicide in this
population appear to be male gender, age under 30 years, depressive
symptoms, unemployment, and recent hospital discharge.[^1]

Currently, there are no drugs approved for the treatment of suicidal
patients with schizophrenia or schizoaffective disorder. If this
supplement is approved, Clozaril will be the only agent approved for
this indication.

**B. Administrative History**

Clozapine is an atypical antipsychotic that has been marketed in the
U.S. since 1990 as Clozaril for the treatment of neuroleptic-resistant
schizophrenia. Since clozapine had demonstrated the potential to cause
agranulocytosis, Clozaril has been distributed under a controlled system
to ensure regular monitoring of WBC counts in all patients receiving
this drug. All Clozaril-treated patients in this country must be
registered in the Clozaril National Registry (CNR).

A few years after the launch of Clozaril in the U.S., data from the FDA
Spontaneous Reporting System database suggested an increased all-cause
mortality, increased mortality due to acute cardiovascular events, and
an increased incidence of pulmonary embolism associated with
clozapine.[^2] To more formally investigate these safety findings, the
innovator company (then Sandoz Pharmaceuticals Corporation) contracted
with Epidemiology Resources, Inc. (ERI) to perform a retrospective study
of overall and cause-specific mortality in current and former users of
Clozaril from CNR data.

One finding that emerged from this study was a markedly reduced risk of
death due to suicide (approximately seven-fold) in current compared to
past users of Clozaril.[^3] Based on this finding as well as a published
study by Meltzer and Okayli that purported to show a reduced risk of
suicidal behavior during Clozaril treatment compared to pre-Clozaril,
Sandoz submitted a supplement (S-028) to describe this finding in
Clozaril labeling. They further requested that the Agency consider
expanding the indication for Clozaril (i.e., for any schizophrenic
patient, regardless of neuroleptic-responsiveness, who exhibits
suicidality or hopelessness).[^4]

Upon review, we found these findings to be difficult to interpret for
various reasons, in particular the fact that the neither study compared
randomized samples.[^5] Thus, we felt that it would be premature to
place this information in labeling at that time.

The sponsor elected to conduct a prospective study to more definitively
demonstrate that Clozaril treatment was associated with a reduced risk
of suicide. Representatives of Sandoz as well as two consultants to
Sandoz (Dr. Herbert Meltzer and Dr. Alexander Walker) met with the
Division on 1-13-97 to discuss a proposed protocol for such a study.
Important points conveyed to the sponsor at this meeting included the
following:

• there was a concern on the part of the Division that suicidality in
patients with schizophrenia may be a pseudospecific phenomenon, i.e., a
clinical symptom common to many disorders that is "specific" to
schizophrenia in name only as opposed to a distinct clinical entity
unique to schizophrenia; if that is the case, a new indication would not
be allowed.

• there was a high standard to gain a comparative claim; we would have
to be reassured that any between-drug differences were not due to an
unfair comparison.

• inclusion of non-treatment resistant patients would be acceptable but
results should be presented by subgroup to assess for any interaction
with this factor.

• open-label drug administration with a blinded rater of suicidality
could be problematic since unblinding of this rater might occur by
virtue of medication side effects or hallway conversations.

• labeling of the study results under Indications mandates a higher
level of evidence compared to a description of the results under
Clinical Trials.

• suicide attempts could be used as a surrogate for completed suicides.

• measures should be taken to minimize the number of patients lost to
follow-up.

On 1-16-98, the sponsor (Novartis Pharmaceuticals Corporation at this
point) submitted the protocol for a 24-month, prospective, randomized
comparison of Clozaril vs. Zyprexa with respect to suicidality in 900
patients with schizophrenia or schizoaffective disorder (study ABA 451).
I reviewed this protocol on 1-28-98. Supervisory comments were appended
by Dr. Thomas Laughren on 1-29-98, and biometrics comments were provided
by Dr. David Hoberman in a 2-10-98 E-Mail. The results from this study
form the basis for this sNDA.

Study ABA 451 was initiated on 3-19-98.

A number of protocol amendments to ABA 451 were subsequently submitted
by the Novartis. Two important amendments are summarized below:

• Amendment #6 was submitted on 1-2-01. This amendment provided for
changes in the primary outcome variable and the primary statistical
analysis. The Division met with the sponsor on 5-16-01 to discuss this
amendment and reach agreement on its acceptability. This amendment will
be discussed in detail in the review of study ABA 451 below.

• Amendment #9, dated on 3-14-00, allowed patients who had dropped out
of the study to later re-enter if certain conditions were met. I
reviewed this change on 3-24-00 and found it to be unacceptable due to
potential confounding of the efficacy analysis. The sponsor was advised
to not implement this change in a 5-1-00 letter from the Division.

The last patient in study ABA 451 completed participation on 2-13-01.

A pre-sNDA meeting was held with the sponsor on 9-5-01. The following
issues were discussed at this meeting:

• we suggested that the primary analysis should be based on the WLW
method with c fixed at 0.5 and the expanded definition for Type 2 Events
(see the review of ABA 451 below for details). Other analyses would be
considered supplementary.

• we indicated that the sNDA would likely be granted priority status and
be taken to the Psychopharmacological Drugs Advisory Committee (PDAC).

• an ISS and ISE would not be needed for this sNDA.

• safety data from only study ABA 451 was required but all relevant
information pertaining to suicidality, including published literature,
should be submitted.

• after our review of an advance listing of all serious adverse events,
we would inform them of which patients warranted submission of a full
complement of clinical data (e.g., Case Report Forms).

• we requested a listing of all patients with Type 1 or Type 2 Events,
from which we would select a random sample for auditing.

• we stated that if a new indication is granted, it would encompass both
refractory and non-refractory patients since both types of patients were
studied.

Novartis submitted a draft copy of the study report for

ABA 451 on 12-21-01 and requested our feedback. A request for further
information was E-Mailed to the sponsor by the FDA Project Manager,
Steve Hardeman, on 1-29-02 and included the following items:

• a in-depth analysis of concomitant psychotropic drug use during the
study.

• a listing of the median dose and dose range for each treatment arm by
visit.

• primary efficacy analyses for the schizophrenia and schizoaffective
disorder subgroups separately.

Novartis submitted this sNDA on 2-28-02.

At a meeting of the review team on 4-4-02, it was decided to file this
sNDA with Priority review status.

**C. Proposed Instructions for Use**

The proposed instructions for use in patients with schizophrenia or
schizoaffective disorder with suicidality are essentially identical to
those recommended in current labeling for patients with
treatment-resistant schizophrenia.

**II. Clinically Relevant Findings from Other Disciplines and from
Consultants**

**A. Statistical Review and Evaluation**

The Statistical Review and Evaluation is pending completion at this
time.

**B. DSI Clinical Site Inspections**

The following four centers from study ABA 451 were inspected by the
Division of Scientific Investigations (DSI): 107, 114, 302, and 956. The
report of the DSI site inspections is not yet complete.

**III. Human Pharmacokinetics and Pharmacodynamics**

No new data regarding human pharmacokinetics or pharmacodynamics have
been submitted for review in this supplement.

**IV. Description of Clinical Data Sources**

The primary source of clinical data for this supplement is study ABA
451, also known as the International Suicide Prevention Trial or
InterSePT. Efficacy data from this trial is discussed in section VI and
safety data is discussed in section VII of this review.

# A. Study ABA 451

**1. Study Design/Enumeration of Patients**

Study ABA 451 was a prospective, randomized, open-label, 24-month trial
in patients with DSM-IV schizophrenia and schizoaffective disorder who
were deemed to be at high risk for suicide.

A total of 980 patients were randomized to either Clozaril or Zyprexa in
a 1:1 ratio (490 patients per arm).

**2. Demographic Characteristics**

The baseline demographic characteristics of the patients in study ABA
451 are displayed in **Appendix IV-1**.

The Clozaril and Zyprexa treatment groups were almost identical in terms
of age, gender, and racial composition. Among patients with baseline
body weight information, the two groups were very comparable in terms of
weight when stratified by gender.

**3. Extent of Exposure**

The suggested dosage range for Clozaril in study ABA 451 was 200-900
mg/day and, for Zyprexa, 5-20 mg/day. In the Clozaril group, the overall
mean daily dose was 308.7 mg (SD= 555 mg). Among Zyprexa-treated
patients, the overall mean daily dose was 17.0 (SD= 25.5 mg).[^6]

The overall exposure in terms of treatment duration is summarized in
**Appendix IV-2**. In all, 304 Clozaril patients and 312 Zyprexa
patients received study drug for at least 631 days. Patient-years of
exposure were not provided.

**B. Published Literature**

The sponsor performed a literature search of the following databases:
Medline (1966-date), Biosis (1993-date), Embase (1974-date), Psycinfo
(1887-October 3, 2001), Derwent Drug File (1983-2001), and Sandoz
Medical Document (1966-date). These databases were searched using the
following string: "(clozapine or Clozaril or Leponex) and (suicide)."

Additionally, an independent internet search using PubMed was conducted
utilizing the search terms "clozapine and suicide" and "clozaril and
suicide."

Finally, the sponsor located an additional eight papers in the review of
the reference lists of identified articles.

Altogether, 70 articles were identified by these searches and were
reviewed by the sponsor. Among these, 34 were deemed to be relevant to
the effects of Clozaril on suicidality. Of the pertinent articles, 11
described studies, 6 consisted of case reports and observational data,
and 17 were review articles of previously published data on suicidality
and clozapine.

Case reports cannot provide persuasive evidence of efficacy in
suicidality and the review articles contained no data or references not
presented in the other papers. Thus, this review will summarize findings
of the 11 investigations describing studies of clozapine and
suicidality.

**V. Clinical Review Methods**

**A. Items Utilized in the Review**

**Appendix V-1** lists the items that were utilized in this review.
Also, relevant information from the Division File for IND 8,333 was
examined.

Case Report Forms and Narrative Summaries were not submitted for all
patients who experienced a serious adverse event (SAE). There were about
1500 adverse experiences classified by the sponsor as "serious" in study
ABA 451. Many of these were classified as serious solely by virtue of
hospitalization for exacerbation of the primary psychiatric illness.
Thus, a listing of all serious adverse events (SAE's) was examined by
the undersigned prior to the sNDA submission to identify those events
which warranted submission of a Case Report Form and Narrative Summary.
This determination was based on a consideration of the expected clinical
seriousness of the events and knowledge of those events already known to
be associated with clozapine treatment. The selected adverse events are
listed in **Appendix V-2**.

**B. Methods Used to Evaluate Data Quality**

The quality of data pertaining to efficacy (suicidality risk) in this
supplement was evaluated by examination of randomly selected Case Report
Forms. Additionally, a search was conducted for any blinded psychiatrist
who had become unblinded during study ABA 451. These two assessments are
further described in **section VI.E** below.

The quality of safety data was assessed by an audit of randomly selected
Case Report Forms submitted for patients in study ABA 451 who died or
experienced other designated serious adverse events. Also, the
appropriateness of the coding of reported adverse event terms to MedDRA
preferred terminology for patients in study ABA 451 was evaluated by the
undersigned. These assessments are further described in **section
VII.D** below.

Data quality was also assessed by the Division of Scientific
Investigations via on-site inspections of four centers from Study ABA
451 (107, 114, 302, and 956). That inspection report is pending
completion at this time.

**C. Adherence to Accepted Ethical Standards**

According to the study report (page 19), study ABA 451 was performed in
accordance with Good Clinical Practice (GCP) standards.

Additionally, Novartis certifies that it did not and will not use in any
capacity the services of any individual debarred under section 306 of
the Federal Food, Drug, and Cosmetic Act in connection with this
application.

**D. Evaluation of Financial Disclosure**

Financial disclosure information was requested by the sponsor from
principal investigators, blinded raters, and members of the Suicide
Monitoring Board (SMB) and Steering Committee (SC).

The following proportions of these individuals responded to the requests
by the time this supplement was completed:

• 74% (60/81) of the principal investigators.

• 46% (80/174) of the blinded raters.

• 100% (3/3) of the SMB members.

• 84% (5/6) of the SC representatives.

Novartis states that due diligence is continuing to be exercised to
collect financial disclosure information for all principal investigators
and blinded raters.

Four principal investigators reported disclosable financial arrangements
and interests:

• Vinod Kumar, M.D., of center 115, received consulting fees from the
sponsor and began full-time employment with Novartis on 3-26-01.
Involvement in study ABA 451 ended on 8-23-00. This center enrolled 4
patients (2 treated with Clozaril and 2 with Zyprexa).

• Alan I. Green, M.D., of center 116, has received support from Novartis
as the principal investigator in other ongoing clinical trials as well
as grants for other research. This center enrolled 12 patients (6
treated with Clozaril and 6 with Zyprexa).

• George T. Grossberg, M.D., of center 120, has received grants for
ongoing research and honorarium from Novartis. This center enrolled 14
patients (7 treated with Clozaril and 7 with Zyprexa).

• Herbert Meltzer, M.D., of center 129, has received research grants
from Novartis for a number of projects. This center enrolled 13 patients
(7 treated with Clozaril and 6 with Zyprexa).

It is unlikely that these arrangements biased the study results since
none of these individuals were raters of suicidality and each of these
sites contributed a small fraction of the total patient sample.

**VI. Integrated Review of Efficacy**

**A. Overview of Data Relevant to Efficacy**

The demonstration of the efficacy of Clozaril in reducing suicide risk
in schizophrenic patients at high risk for suicidality rests on the
results of a single, prospective clinical trial, study ABA 451. This
study is reviewed in detail below.

As mentioned above, the sponsor's literature search revealed 11
published investigations that produced clinical data relevant to a
purported anti-suicide effect of Clozaril. These studies are summarized
below. Based on my review of each investigation, they all suffer from
significant flaws that render them incapable of providing convincing
evidence of an anti-suicide effect.

**B. Study ABA 451**

**1. Investigators/Sites**

In all, 67 centers worldwide enrolled patients in study ABA 451 (31 U.S.
centers and 36 foreign centers). The location, number of randomized
patients by treatment group, and principal investigator(s) for each of
these centers are listed in **Appendix VI-1**.

No principal investigator (PI) was listed as disqualified by the Agency
as of 7-16-02.

**2. Objectives**

The primary efficacy objective was to demonstrate a decreased risk for
suicide among schizophrenic patients treated with Clozaril compared to
the risk among patients treated with Zyprexa.

**3. Study Population**

A total of 980 patients were randomized to treatment with either
Clozaril or Zyprexa in study ABA 451: 396 patients were randomized in
the U.S. centers (198 each to Clozaril and Zyprexa) and 584 were
randomized in foreign studies (292 each to Clozaril and Zyprexa).

Important inclusion criteria were:

• male or female patients, age 18-65, meeting DSM-IV criteria for
schizophrenia or schizoaffective disorder.

• at high risk for suicidality as indicated by one of the following:

> **-** attempted suicide within 3 years of study baseline assessments.
>
> **-** hospitalized to prevent a suicide attempt within 3 years of
> baseline assessments.
>
> **-** moderate to severe suicidal ideation with a depressive component
> within one week of baseline assessments.
>
> **-** moderate to severe suicidal ideation with command hallucinations
> to do self-harm within one week of baseline evaluation.

Although Clozaril is approved only for treatment-resistant schizophrenia
in the U.S., patients were enrolled in this trial irrespective of
treatment-responsiveness.

Important exclusion criteria were:

• judged to be incompetent to make treatment decisions or refusal to
agree to participation.

• no previous exposure to antipsychotic medication.

• extreme psychosis requiring immediate treatment.

• pregnancy or nursing a child.

• highly suicidal patients were not randomized until their condition was
stabilized.

Additionally, enrollment of the following patients was discouraged:

• previous inadequate response to adequate doses of Clozaril (≥600
mg/day) or Zyprexa (≥10 mg/day) for at least 4 weeks.

• good clinical response to either Clozaril or Zyprexa, since they could
be randomized to less effective medication.

• requiring complicated regimens of multiple medications.

• history of poor compliance with treatment plans.

**4. Study Description**

[Design]{.underline}

This was a prospective, randomized, open-label, 24-month trial with two
active treatment arms, clozapine (Clozaril) and olanzapine (Zyprexa).
Eligible patients were randomized in a 1:1 ratio to Clozaril or Zyprexa
within each study center. Patients and PI's were not blinded during this
study but each site did include blinded raters for efficacy and
suicidality assessments.

[Dosing and Concomitant Medications]{.underline}

All study medication was dispensed at the investigational site. The
recommended starting dose for Clozaril was 12.5mg bid with a suggested
target dose range of 200-900 mg/day. The recommended starting dose for
Zyprexa was 5 mg/day with a recommended target dose range of 5-20
mg/day. All patients were titrated to their most effective dose as
tolerated. The doses used were to reflect the community norm.

Patients who entered the trial while receiving other antipsychotics were
to be cross-titrated. The prior medication was to be weaned as the dose
of study medication was titrated to therapeutic levels. Cross-titration
was to be completed within 30 days of randomization if possible.
Patients who had received depot medication were to be randomized once a
full dosing interval had passed.

Randomized patients were allowed to take any medication deemed medically
necessary and appropriate by the PI, to include the judicious use of
antidepressants to treat worsening suicidal ideation or depression
during the trial.

[Assessments]{.underline}

The PI conducted scheduled assessments of suicidality (i.e., completion
of the InterSePT Suicidal Thinking and the CGI Severity of Suicidality
scales) on a frequent basis.[^7] However, information pertaining to a
completed suicide, suicide attempt, hospitalization due to imminent
suicide risk, or (for inpatients) an increased level of surveillance due
to suicidality was collected throughout the 104 week treatment period
and recorded in the CRF by the PI. Data relevant to suicides and suicide
attempts were documented on the Suicide Attempt Form (SAF). Data
relevant to hospitalization or increased surveillance due to imminent
suicide risk were documented on the Imminent Risk of Suicide Requiring
Hospitalization (IRH) form.

Psychiatrists at each site who were blinded to the patient's treatment
(Blinded Psychiatrists or BP's) conducted the same assessments of
suicidality on a less frequents basis.[^8]

Additional efficacy measures (PANSS, CGI for Change in Psychosis, CGI
for Severity of Psychosis, Calgary Depression Scale) were performed by
blinded raters who could also have acted as the blinded psychiatrists.

[Dropouts]{.underline}

If a patient discontinued participation in the study for any reason, the
PI was to attempt to follow the patient by regular contact with the
patient or the patient's family to determine if the patient completed or
attempted suicide or was hospitalized for imminent risk of suicide. This
follow-up period was to extend to what would have been Week 104 of the
patient's treatment. Patients could elect not to be contacted during
this period. Patients who consented to this follow-up were considered
Retrieved Dropouts (RDO's) and assessments of suicidality by the
unblinded PI were done every 12 weeks. Assessments on RDO's included the
ISST-PI (InterSePT Scale for Suicidal Thinking-Principal Investigator)
and the CGI-SS-PI (Clinical Global Impression of Severity of
Suicidality-Principal Investigator); as indicated, the SAF (Suicide
Attempt Form) and the IRH (Imminent Risk Requiring Hospitalization) form
were also completed. All RDO assessments were completed by unblinded
study staff.

Amendment #10 to the study protocol, submitted on 3-14-00, permitted the
return of patients who had dropped out due to mild adverse events, loss
to follow-up, transportation difficulties, and exacerbation of illness
due to noncompliance, among other reasons, to resume study participation
on the drug to which they were originally randomized at the study
timepoint at which they had dropped out. Such patients had to request to
resume study participation and continue to meet all eligibility
criteria. Also, the treating physician must have deemed resumption of
study treatment in the best interest of the patient.

Novartis was advised by the Division in a 5-1-00 letter that this
amendment was considered likely to confound the assessment of
suicidality in this study for several reasons, such as the introduction
of a variable (a break in treatment that may include other interim
therapy) which could influence the occurrence of suicidality later in
the trial. Therefore, the Division recommended that this amendment not
be implemented. Despite this advice, it appears that the sponsor
implemented this protocol change.

[Maintenance of Blinding]{.underline}

It was considered possible that any decrease in suicidality observed in
Clozaril patients might be due to the frequent contact with healthcare
professionals consequent to the mandatory WBC monitoring with Clozaril.
WBC monitoring was performed weekly for the first 26 weeks then every 2
weeks thereafter. To balance this potential source of bias between the
two groups, Zyprexa patients were also seen on this same schedule for
vital sign measurements. Also at these visits, an unblinded healthcare
professional assessed the patient's overall psychiatric condition, to
include suicidality, and referred the patient to the investigator or
other professional for further evaluation and possible intervention when
deemed appropriate.

As noted above, patients and PI's were not blinded. To address the
possibility of biased assessments of primary outcome occurrences (Type 1
and Type 2 Events), the following measures were instituted.

First, as mentioned above, each site included a psychiatrist who was
blinded to the patient's treatment. Ratings on the CGI-SS-BP, to detect
a possible Type 2 Event, were performed by the blinded psychiatrist.
These individuals affirmed their blinded status or indicated unblinding
at each assessment.

Second, the flow of data pertaining to a possible Type 1 event was
designed to help assure unbiased detection and confirmation of these
events. The relevant personnel and study features are described in
detail below.

PI's collected and forwarded all relevant information on any potential
Type 1 event to Ingenix Pharmaceutical Services, Inc., a contract
research organization. This included information on all deaths, suicide
attempts, psychiatric hospitalizations, discontinuations of study drug,
and increased surveillance due to imminent suicide risk. Blinded reviews
of the study clinical database were also performed by Ingenix to
identify any potential Type 1 events that might have been missed.

Ingenix reviewed the data from the study site and censored any
information that was likely to unblind the reader to the patient's
treatment, to include signs or symptoms that might unwittingly reveal
the patient's treatment. The data were then forwarded to the BP's and to
the Suicide Monitoring Board (SMB).

The SMB was a blinded body comprised of three clinicians who are experts
in the study of suicide with experience in schizophrenia. The SMB
Chairman was Ranga Krishnan, M.D., Duke University Medical Center,
Durham, NC; SMB members were Hannele Heila, M.D., National Public Health
Institute, Helsinki, Finland, and Isaac Sakinofsky, M.D., University of
Toronto, Toronto, Canada.

Under no circumstances was the SMB to be unblinded to the treatment of
any study patient. If any member of the SMB became unblinded, the SMB
Chairman was to be notified who, in turn, would notify Novartis.

The primary purpose of the SMB was to make determinations regarding the
blinded data received from Ingenix as follows:

• for all deaths, to judge whether the death represented a suicide.

• for all self-damaging acts, regardless of intention, to determine if
the act represented a serious suicide attempt as opposed to a suicide
gesture or non-attempt.

• for all hospitalizations and increases in the level of surveillance
for suicide, to ascertain whether these represented interventions to
prevent an imminent suicide attempt.

• for all discontinuations from study drug treatment due to increasing
suicidality, to determine whether discontinuation occurred because of
imminent suicide risk.

The SMB conducted regular teleconferences to discuss blinded data from
Ingenix and to reach consensus on each event. If there was disagreement
on a determination, a vote was to be taken and the final determination
was defined as that of the majority of the SMB members.

Although blinded data from Ingenix for all potential Type 1 events were
also reviewed by the BP's, the determination of the SMB regarding the
presence or absence of a Type 1 event was considered primary for
purposes of efficacy analysis.

[Steering Committee]{.underline}

Oversight and guidance for study ABA 451, with the purpose of minimizing
risk to study participants and maintaining the scientific integrity of
the trial, was provided by the study Steering Committee (SC). Although
the SC interacted with a liaison from Novartis (Ravi Anand, M.D.), this
committee was considered to be an independent body. The SC was comprised
of the Chairman, John Kane, M.D., and members Daniel Casey, M.D., Prof.
Frederic Rouillon, Prof. Giovanni Cassano, Prof. Shon Lewis, Prof.
Istvan Bitter (resigned November 2000), and Nancy Temkin, Ph.D.

**5. Efficacy Analysis Plan**

The efficacy analysis plan for this study has been amended from that
specified in the original protocol. In the original protocol, two
primary variables were specified:

• time from baseline to the first significant suicide attempt or
hospitalization due to imminent risk of suicide confirmed by the
SMB.[^9] This analysis was to be performed using a Cox proportional
hazards regression model. Explanatory variables were treatment and the
following baseline measures: number of lifetime suicide attempts, active
substance/alcohol abuse, pooled country, sex, and age (18-32 years,
33-44 years, and 45 years and older).

• change from baseline in the CGI-SS-BP severity score as rated on a
5-point scale. These data were to be analyzed using an ANCOVA model with
the same explanatory variables listed above as well as the baseline
CGI-SS-BP severity score.

During the course of study ABA 451, Novartis found that the rate of
suicides and suicide attempts was lower than predicted and the rate of
loss to follow-up was higher than predicted when the sample size for the
trial was computed. Additionally, the sample size calculation did not
account for the need to adjust the significance level for multiple
comparisons, given that there were two primary efficacy variables. As a
result of these factors, Novartis felt that 80% power to detect a
intergroup difference would not be achieved and, therefore, it would be
more likely that this trial would fail to demonstrate the superiority of
Clozaril over Zyprexa in reducing suicidality.

To address this concern, the sponsor convened a group of clinical and
statistical experts in August 2000. It was recommended that specific
revisions to the primary study objectives and statistical analysis plan
be implemented as described below. These changes comprised Amendment #6
to the protocol, which was submitted to the Agency on 1-2-01.

The revised study objective was to demonstrate a decreased risk for
suicide among schizophrenic patients treated with Clozaril compared to
patients treated with Zyprexa as measured by the time (in days after
randomization) to the following two types of events:

[Type 1 Event]{.underline} -- a significant suicide attempt or completed
suicide, hospitalization due to imminent suicide risk, or increased
surveillance due to suicide risk, whichever came first and regardless of
whether the subject was still on randomized treatment. If none of these
events occurred during the entire study period, time was censored on the
date of study drug discontinuation or on the last date of retrieved
data, whichever was later.[^10]

[Type 2 Event]{.underline} -- 1) worsening of the severity of
suicidality as manifested by a score of 6 or 7 (worse or very much
worse) on the 7-point change score of the Clinical Global Impression for
Severity of Suicidality as rated by a blinded psychiatrist (CGI-SS-BP)
or 2) the occurrence of a Type 1 Event, whichever came first and
regardless of whether the subject was still on randomized treatment. If
neither event occurred throughout the entire study period, time was
censored on the date of study drug discontinuation or on the last date
of retrieved data, whichever was later.

The revised primary analysis was based on the approach of Wei, Lin, and
Weissfeld, known as the WLW method.[^11] Using this multiple events
analysis technique, the time to the first occurrence of a Type 1 event
and time to the first occurrence of a Type 2 event were modeled using a
proportional hazards approach to derive treatment effect estimators for
each event type, with country pool as strata and treatment group as the
only covariate.[^12] The WLW method provided a single test for treatment
effect based on two time to event endpoints, with the two event types
given equal weighting in this case. Then, a two-sided test was performed
at the 0.05 level of significance to compare the combined treatment
estimators between the two treatment groups.

A number of supplemental analyses were also performed, to include the
following:

• the original primary efficacy analyses, as described above.

• analysis of time to Type 1 events using a full Cox proportional
hazards regression model adjusted for a number of baseline factors,
which permitted assessment of the effect of these factors on time to
event.

• analyses for diagnostic subgroups, i.e., patients with schizophrenia
versus patients with schizoaffective disorder.

• analyses for geographic subgroups, i.e., North America versus the rest
of the world.

**6. Baseline Patient Characteristics**

At baseline, the Clozaril and Zyprexa treatment groups were comparable
in terms of mean PANSS total scores (84.8 vs. 82.6, respectively).

With respect to suicidality, the two treatment arms had almost identical
distributions of CGI-Severity of Suicidality scores as rated by the
blinded psychiatrists (**Appendix VI-2**). On average, Clozaril patients
had a lifetime history of 3.6 suicide attempts compared to 3.2 suicide
attempts among Zyprexa patients. About 15% of each group had no history
of previous suicide attempts and another 15% of each group had a history
of more than 5 suicide attempts. The median number of lifetime
hospitalizations to prevent a suicide attempt was 2 in each treatment
arm.

Baseline demographic characteristics are displayed in **Appendix IV-1**.
The treatment groups were almost identical in terms of age, gender, and
racial composition.

Diagnostically, 61% (300/490) of Clozaril and 63% (309/490) of Zyprexa
patients were diagnosed with schizophrenia; 39% (190/490) of Clozaril
and 37% (181/490) of Zyprexa patients were diagnosed with
schizoaffective disorder. About one-fourth of each group was considered
treatment-resistant by clinical assessment.

About one-half of each treatment group had a history of alcohol or other
substance abuse (48% of Clozaril and 51% of Zyprexa patients). At
baseline, 11% of each group had current alcohol or other substance
abuse.

The baseline mean total scores for the Calgary Depression Scale (CDS)
were very similar between groups: Clozaril= 9.8 (SD=5.9), Zyprexa= 9.9
(SD=5.9). The percentages of patients with each score on the
Hopelessness item (item #2) of the CDS were also similar between the two
groups at baseline.

**7. Patient Disposition**

A total of 1,065 patients were screened for study ABA 451. Of these, 980
were randomized to Clozaril (N=490) or Zyprexa (N=490) and comprised the
intent-to-treat (ITT) population.

In all, 61% (298/490) of the Clozaril and 62% (303/490) of the Zyprexa
patients completed the entire 2 year study. Including retrieved
dropouts, 39% (192/490) of the Clozaril and 38% (187/490) of the Zyprexa
patients discontinued from the study. These dropouts are enumerated by
reason for discontinuation in **Appendix VI-3**. It is notable that 33
Clozaril and 39 Zyprexa patients were lost to follow-up. It is not known
if any of these patients were lost due to suicide attempts or completed
suicide.

The numbers of patients in the study by visit are displayed in
**Appendix VI-4**. At least 70% (344/490) of Clozaril patients were
still in-study at the week 40 visit, with 76% (370/490) of the Zyprexa
patients still participating at that timepoint.

**8. Dosing Information**

Ten of the Clozaril patients and 11 of the Zyprexa patients in the ITT
population were not dispensed study drug. Also, one of the Clozaril
patients and 2 of the Zyprexa patients who were dispensed drug did not
take study medication.

Among the 479 Clozaril patients who took study drug, the overall mean
daily dose was 308.7 mg (SD= 555 mg). The mean prescribed doses of
Clozaril gradually increased from 150 mg/day at week 1 to just under 300
mg/day at week 12; thereafter, mean prescribed doses were in the range
of 300 to 334 mg/day, with a maximum of 800 or 900mg/day.

Among the 477 Zyprexa patients who took study drug, the overall mean
daily dose was 17.0 mg(SD= 25.5 mg). Mean prescribed doses of Zyprexa
gradually increased from 12 mg/day at week 1 to about 17 mg/day after
week 10; mean doses remained in the range of 17 to 18 mg/day for the
remainder of the trial, with maximum doses of generally 50 mg/day.

Median prescribed doses by visit are presented in **Appendix VI-5**.
From week 10 onward, the median doses of Clozaril and Zyprexa were 300
and 20 mg/day, respectively.

**9. Concomitant Medications**

Patients who entered the study while taking other antipsychotic
medication were to be cross-titrated within 30 days of randomization.
Also, after randomization, concomitant psychotropic medications were
permitted by protocol if deemed necessary and appropriate by the
investigator. Psychopharmacologic agents were used by a substantial
proportion of patients during the study. For example, among the 479
Clozaril and 477 Zyprexa patients who took study medication, concurrent
selective serotonin reuptake inhibitors were used by 39% of Clozaril and
46% of Zyprexa patients. Also, it is notable that 5 patients randomized
to Zyprexa received Clozaril concomitantly and 16 patients randomized to
Clozaril received Zyprexa concomitantly.

The concomitant use of psychopharmacologic agents during this trial
could confound the assessment of an anti-suicide effect. To better
appreciate the extent of this potential source of bias, the Division
requested that Novartis devise a method to demonstrate that the use of
concomitant psychotropic medication is unlikely to have biased the
results of study ABA 451. The plan devised by the sponsor and the
results of this analysis are described below.[^13]

[Analysis Plan]{.underline}

The sponsor grouped concomitant psychotropic medication used in study
ABA 451 into the following groups: antidepressants, antipsychotics,
sedatives/anxiolytics, and mood stabilizers. Stimulants and
anti-dementia drugs were excluded. Once a medication was assigned to one
of the above classes, all uses were included in the analysis (both
psychiatric and non-psychiatric indications). However, medication usage
based on a PRN schedule was excluded as were antidepressants and mood
stabilizers taken for less than 14 days.

To pool the use of medications of different potencies within a class,
the dosage of each drug was converted to dosage equivalents within each
class based on conversion data and average doses reported in current
literature. Antidepressants were converted to fluoxetine equivalents,
sedatives/anxiolytics to diazepam equivalents, antipsychotics to
haloperidol equivalents, and mood stabilizers to carbamazepine
equivalents.

Then, the total AUC (sum of the areas under the converted dosage versus
time curves for all drugs within a class) over successive 6 month
intervals was calculated for each patient for each concomitant drug
class.

Next, the mean dose per patient for each class was calculated by
dividing the total AUC by the number of days in-study for that patient
during each 6 month interval. For dropouts, no mean dose was computed
after the end of the 6 month interval in which the patient dropped out.

Finally, for each drug class and each interval, the average mean dose
was determined over all patients. ANCOVA, with terms for treatment,
pooled country, and concomitant medication dose at baseline, was
performed to compare the least squares mean dosage (LSMD) between
treatment groups for each 6 month interval, with statistical
significance defined as a p-value ≤0.05.

[Analysis Results]{.underline}

Of all patients who took study drug (N=956), a large proportion took
psychopharmacologic drugs concomitantly and were included in the
analysis: 84% took antipsychotics, 65% took sedative/anxiolytics, 53%
took antidepressants, and 28% took mood stabilizers. **Appendix VI-6**
enumerates these patients by treatment group.

Pooling data across all 6 month intervals, the LSMD's for Clozaril were
significantly less than for Zyprexa for all four drug classes
(**Appendix VI-7**).

A breakdown of the LSMD's by 6 month intervals is provided in **Appendix
VI-8** (for antipsychotics), **Appendix VI-9** (antidepressants),
**Appendix VI-10** (sedatives/anxiolytics), and **Appendix VI-11** (mood
stabilizers). For most comparisons, the LSMD for Clozaril was less than
for Zyprexa to a statistically significant degree. For the remainder of
the comparisons (i.e., antidepressants during months 13-18 and 19-24 and
mood stabilizers during months 19-24), the LSMD's was numerically less
for Clozaril than for Zyprexa.

In sum, the sponsor's analysis revealed no evidence to suggest a bias
due to concomitant medication usage that favored Clozaril over Zyprexa.
These results should be interpreted with a large grain of salt since
this analysis is based on an imperfect surrogate measure for the
confounding influence of concomitant psychotropic medication on
suicidality.

**10. Protocol Deviations**

A common protocol deviation was a change in clinical raters during the
study. In particular, it was noted that 42% of the Clozaril patients and
44% of Zyprexa patients had a change in the rater for the CGI-SS-BP
during their trial participation, which included an assessment by a
blinded psychiatrist of the change in suicidality compared to the
patient's condition at baseline. The reliability of this specific
rating, which was one of the key outcome variables, may have been
compromised by the changes in raters for this scale. The extent to which
this was true is very difficult to gauge.

**11. Study Results**

[Psychotic Symptomatology]{.underline}

Both treatment groups experienced improvement in psychotic
symptomatology as measured by changes from baseline to end of study
(LOCF) in the PANSS total score (-23.6 for Clozaril and --22.4 for
Zyprexa; p-value= 0.3591). The PANSS positive and negative subscales and
the CGI for severity of psychosis (CGI-SP) provided further evidence of
improvement for both Clozaril and Zyprexa patients.

[Enumeration of Patients with Type 1 & Type 2 Events]{.underline}

The numbers and percentages of patients with Type 1 events, as
determined by the SMB, and Type 2 events, as determined by the BP's, are
displayed in **Table VI-1** below. In the primary analysis, any Type 1
event was taken to imply a Type 2 event; thus, patients with a Type 1
event are a subset of the patients with a Type 2 event. Clearly, the
predominant event type was Type 1. For both event types, the proportion
of patients with the event was significantly lower in the Clozaril
compared to the Zyprexa group.

+-------------------------+---------------+---------------+------------+
| **table vi-1**          |               |               |            |
|                         |               |               |            |
| **number (%) of itt     |               |               |            |
| patients with type 1    |               |               |            |
| and type 2 events**     |               |               |            |
+-------------------------+---------------+---------------+------------+
| **Event Type**          | **Clozaril**  | **Zyprexa**   | **p-va     |
|                         |               |               | lue**[^14] |
|                         | **(N=490)**   | **(N=490)**   |            |
+-------------------------+---------------+---------------+------------+
| Type 1                  | 102 (20.8%)   | 141 (28.8%)   | 0.0049     |
+-------------------------+---------------+---------------+------------+
| -Completed Suicide      | 5 (1.0%)      | 3 (0.6%)      | 0.7254     |
+-------------------------+---------------+---------------+------------+
| -Suicide Attempt        | 34 (6.9%)     | 55 (11.2%)    | 0.0257     |
+-------------------------+---------------+---------------+------------+
| -Hospitalization        | 82 (16.7%)    | 107 (21.8%)   | 0.0518     |
+-------------------------+---------------+---------------+------------+
| Type 2                  | 120 (24.5%)   | 161 (32.9%)   | 0.0047     |
+-------------------------+---------------+---------------+------------+

[WLW Analysis]{.underline}

The amended primary analysis was a single composite analysis of time to
the first occurrence of a Type 1 event and time to the first occurrence
to a Type 2 event using WLW methodology, as described above, with equal
weighting given to each event type in the model. The analysis was based
on all randomized patients (490 Clozaril and 490 Zyprexa patients).

The results are summarized in **Appendix VI-12**. The coefficient of
combined treatment effect from the primary model was --0.265, with a
p-value for the Clozaril/Zyprexa comparison of 0.0309.[^15] Examining
the WLW treatment effect estimators for Type 1 and Type 2 events
separately, there was a significantly lower risk of each event with
Clozaril versus Zyprexa: the respective hazard ratios (95% CI) were 0.76
(0.58, 0.98) and 0.78 (0.61, 0.99).[^16]

[Original Primary Analysis]{.underline}

As a supplemental analysis, the sponsor also analyzed the results of
this trial utilizing the methods proposed in the original protocol (and
Amendment #1). This entailed examination of two variables: 1) the time
from baseline to the first significant suicide attempt, hospitalization
due to imminent risk of suicide, or an increased level of surveillance
for suicide risk (Type 1 event), using a Cox proportional hazards
regression model; and 2) change from baseline in the CGI-SS-BP severity
of suicidality score as rated on a 5-point scale, analyzed using an
ANCOVA model.

The Type 1 event results were similar to those in the amended primary
analysis: there was a statistically significant lower risk of a Type 1
event among Clozaril versus Zyprexa patients (regression coefficient for
treatment= -0.304, p=0.0211; hazard ratio= 0.74 (95% CI= 0.57, 0.96)).
However, results for the change from baseline in the CGI-SS-BP severity
score were not statistically significant (regression coefficient=
+0.007, p-value= 0.8884).

[Kaplan-Meier Analysis]{.underline}

A secondary analysis was a Kaplan-Meier survival analysis of the
cumulative probabilities of Type 1 events and Type 2 events.
Kaplan-Meier survival curves are displayed in **Appendix VI-13** (Type 1
events) and **Appendix VI-14** (Type 2 events). Survival data by visit
are displayed in **Appendix VI-15**. The cumulative probabilities of
experiencing an event were numerically lower for Clozaril patients than
for Zyprexa patients at all visits for each event type.[^17] At week
104, the cumulative probabilities were significantly lower for Clozaril
(**Table VI-2** below).

+----------------+-----------------+----------------+-----------------+
| **table vi-2** |                 |                |                 |
|                |                 |                |                 |
| **kaplan-meier |                 |                |                 |
| estimates of   |                 |                |                 |
| the cumulative |                 |                |                 |
| probabilities  |                 |                |                 |
| of a type 1 or |                 |                |                 |
| type 2 event   |                 |                |                 |
| at week 104**  |                 |                |                 |
+----------------+-----------------+----------------+-----------------+
| **Event Type** | **Clozaril**    | **Zyprexa**    | *               |
|                |                 |                | *p-value**[^18] |
+----------------+-----------------+----------------+-----------------+
| Type 1         | 0.24            | 0.32           | 0.020           |
+----------------+-----------------+----------------+-----------------+
| Type 2         | 0.28            | 0.37           | 0.027           |
+----------------+-----------------+----------------+-----------------+

**12. Conclusions from Study ABA 451**

The results of study ABA 451 appear, on face, to support the hypothesis
that Clozaril treatment is associated with a reduced risk of suicidality
compared to Zyprexa therapy. However, the validity of this finding is
questionable for several reasons:

1\) the primary efficacy analysis (WLW methodology) included patients
who had dropped out and discontinued study drug but were being followed
as retrieved dropouts. In my opinion, to assess the effect of ongoing
drug exposure on event occurrence, patients included in the analysis
should be receiving drug and patients who drop out of drug treatment
should be right-censored at the time of dropout. Otherwise, and
particularly in a long-term study like ABA 451, it is very tenuous to
ascribe the occurrence or non-occurrence of events to study drug.
Censoring dropouts may significantly change the study outcome.

2\) Amendment #9 to the study protocol allowed patients who had dropped
out of the study to re-enter the trial as full participants at a later
date and continue the originally assigned medication on the study day of
dropout. This change introduced a variable (a break in treatment that
may have included interim interventions) that could have influenced the
risk of suicidality after re-entry of these patients, thus confounding
the efficacy results. It is not known how many patients actually
returned to the study under this amendment.

3\) a number of patients (33 Clozaril and 39 Zyprexa patients) were lost
to follow-up at some point during this trial. It is not known if any of
these patients experienced a suicidality-related event (such as suicide
or a serious suicide attempt) that led to study discontinuation. The
possibility remains that information about the circumstances of
discontinuation in these patients might appreciably change the study
results.

4\) for a sizeable proportion of patients in each group (42% of Clozaril
and 44% of Zyprexa patients), there was a change in the blinded rater
who completed the CGI for severity of suicidality (CGI-SS-BP). A key
outcome variable was the rating of the change in the patient's
suicidality compared to the [baseline]{.underline} condition using this
scale. The reliability of a new rater in assessing change from the
baseline condition is very questionable.

5\) a substantial number of patients took concomitant psychiatric
medication during this study. While it would be expected to see a large
number of such patients taking antipsychotics early in the trial (due to
the cross-titration procedure for patients on antipsychotics at study
entry), it is noted that 273 Clozaril and 279 Zyprexa patients took
concomitant antipsychotics during the last 6 month interval of the study
(months 19-24). During this same interval, antidepressants were taken by
169 Clozaril and 201 Zyprexa patients. It is unknown how many of these
patients were simply continuing pre-study medication versus the number
who were deemed to require the institution of psychotropics for emergent
conditions, such as suicidal ideation, during the study. It is
acknowledged that the sponsor's analysis of concomitant psychotropic
drug use represents a good-faith effort to address this issue and that a
complete understanding of the impact of this usage is likely impossible.
Nonetheless, the inability to fully quantify this potential confounding
influence does not render it ignorable.

6\) as is discussed in detail in section VI.E (Assessment of Efficacy
Data Quality), an audit of the suicidality data from this trial revealed
two potential findings (possible biased SMB determinations and
unblinding) that could impact on the reliability of the data from study
ABA 451.

The above factors raise a considerable question about the validity of
the study findings. At this point in time, the stated findings from
study ABA 451 are best considered inconclusive.

**C. Important Clinical Issues Pertinent to Efficacy**

**1. Suicidality Indication**

According to the proposed INDICATIONS AND USAGE section of Clozaril
labeling, Novartis is seeking approval for the treatment of suicidality
in patients with schizophrenia or schizoaffective disorder. Suicidality
is defined as actions by a patient committed either with willful intent
or as a response to internal compulsions or disordered thinking that put
him/herself at high risk for death.

Evidence for this claim is derived from study ABA 451. This trial
utilized the following inclusion criteria to identify patients at high
risk of suicidality:

• attempted suicide within 3 years of baseline.

• hospitalized to prevent a suicide attempt within 3 years of baseline.

• moderate to severe suicidal ideation with a depressive component
within one week of baseline.

• moderate to severe suicidal ideation with command hallucinations to do
self-harm within one week of baseline.

To be included in this study, a patient had to meet [one]{.underline} of
the above criteria. Thus, the study population was likely quite
heterogeneous at baseline in terms of imminent suicide risk, ranging
from patients with active suicidal ideation and a plan to harm
themselves to patients who were hospitalized 3 years before study
participation for suicidal ideation which has long since resolved.
Clearly, patients were not required to be actively suicidal at the time
of study entry. In fact, according to the study report, patients who
were "highly suicidal" were not randomized until their condition
stabilized.

Critical to the approval of a claim for the treatment of any given
condition is the requirement that the effect of the intervention be
demonstrated [in patients with that condition]{.underline}. Therefore,
to the extent that study ABA 451 included patients who were not suicidal
at baseline, this trial is not capable of providing evidence of the
efficacy of Clozaril in treating suicidality.

Furthermore, the design of ABA 451, which examined the risk of
suicidality-related events over a two year period, would not be
appropriate to demonstrate efficacy in treating acute suicidality. A
claim for the latter would imply an intervention that reduces the risk
of self-harm or death in the short-term (days to a few weeks), not over
a period of years.

In summary, an acceptable study for evaluating a treatment for
suicidality would enroll actively suicidal patients only and anticipate
a response over a relatively brief period of time. ABA 451 is not such a
trial.

On the other hand, the results of ABA 451 may be useful in demonstrating
a reduced risk of suicidality associated with long term Clozaril versus
Zyprexa treatment. The use of Clozaril as a preventive measure in this
regard would be a feasible indication for the sponsor to seek. In that
case, a critical and difficult clinical issue to be addressed is the
identification of patients for whom Clozaril is indicated for the
purpose of suicidality prevention. Since it is anticipated that the
sponsor will amend this application to seek approval of this use, this
issue will be explored further at this point.

The emergence of suicidality is frequently precipitated by external
events (e.g., loss of a significant other person or a financial crisis)
superimposed on various underlying cofactors (such as substance abuse,
depression, or health problems). Unfortunately, due to the unpredictable
nature of these precipitants, there is no reliable way of identifying
those patients who will become suicidal.

As a conservative practice, any patients with a history of any
suicidality might be treated with Clozaril. However, the wisdom of
switching large numbers of patients to Clozaril from otherwise effective
and well-tolerated antipsychotic therapy or choosing to initiate
Clozaril over other drugs that might be better tolerated and perhaps
more effective is debatable. Not to be ignored are the cost,
inconvenience, and discomfort associated with the white blood cell
monitoring required for patients treated with Clozaril.

A better approach would be the use of Clozaril in a more discriminating
fashion, such as in patients with a pattern of chronic suicidal behavior
or suicidal ideation who are deemed to be at some continuing risk of
suicide. It would be difficult to formulate specific criteria for such
use for labeling and, ultimately, this decision should depend on the
judgement of the treating physician, who is capable of considering the
clinical nuances of the patient's history and presentation and weighing
the risks versus potential benefits for the individual patient. But, in
this case, it may be more appropriate to simply describe the results of
study ABA 451 in labeling and allow prescribers to decide, on a
patient-by-patient basis, whether Clozaril is indicated. A potential
downside is that some managed healthcare organizations may refuse to
subsidize the cost of Clozaril and WBC monitoring for these patients
without a formal, labeled indication for such use.

The best solution to this problem is not clear at this time.

**2. Predictors of Response**

[Covariate Analyses]{.underline}

A covariate analysis was performed on data from study ABA 451 to
identify prognostic factors for suicidality using a full Cox
proportional hazards regression model for time to a Type 1 event.
Covariates included the following: treatment, gender, age group (≤32,
33-44, ≥45 years), number of lifetime suicide attempts, diagnosis,
alcohol or other substance abuse, and a number of baseline ratings, to
include the CGI-SS-BP severity score, Calgary Depression Scale score,
and the Covi Anxiety Score.

Results are depicted in **Appendix VI-16**. These analyses revealed that
treatment, the number of lifetime suicide attempts, and the presence of
substance or alcohol abuse were statistically significant prognostic
factors for Type 1 events.

Adjusting for risk factors demonstrated a treatment effect favoring
Clozaril on SMB-confirmed Type 1 events (hazard ratio= 0.73, p-value=
0.0172). Interestingly, when this analysis is applied to the time to
Type 1 events as confirmed by the [blinded psychiatrist]{.underline},
Clozaril has a somewhat larger hazard ratio (0.84) and treatment is no
longer a statistically significant predictor (p=0.1839).[^19]

With respect to the number of lifetime attempts, the hazard ratio was
1.03 (p=0.0001), indicating that an increased number of attempts was
associated with a very slightly increased risk of a Type 1 event.

Regarding substance or alcohol abuse, the hazard ratio was 1.48
(p=0.0081), indicating an association between alcohol or substance abuse
and an increased risk of a Type 1 event.

A similar covariate analysis of time to a Type 2 event revealed
analogous findings.

[Diagnostic Subgroup Analysis]{.underline}

Although the above analysis did not reveal an significant effect of
diagnosis on the time to a Type 1 or Type 2 event, a subgroup analysis
was specifically requested by the Division. The numbers and percentages
of Clozaril and Zyprexa patients with Type 1 and Type 2 events as well
as the Kaplan-Meier cumulative probabilities of events are displayed by
diagnostic subgroup (schizophrenia vs. schizoaffective disorder) in
**Table VI-3** below. For all treatment group comparisons, Clozaril was
numerically superior to Zyprexa in terms of event risk regardless of
diagnosis (formal statistical testing was not performed).

+-------------+--------+--------+--------+--------+--------+--------+
| **table     |        |        |        |        |        |        |
| vi-3**      |        |        |        |        |        |        |
|             |        |        |        |        |        |        |
| **number    |        |        |        |        |        |        |
| (%) of itt  |        |        |        |        |        |        |
| patients    |        |        |        |        |        |        |
| with type 1 |        |        |        |        |        |        |
| and type 2  |        |        |        |        |        |        |
| events by   |        |        |        |        |        |        |
| diagnostic  |        |        |        |        |        |        |
| subg        |        |        |        |        |        |        |
| roup**[^20] |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
|             | **Cloz |        |        | **Zyp  |        |        |
|             | aril** |        |        | rexa** |        |        |
|             |        |        |        |        |        |        |
|             | **(N=  |        |        | **(N=  |        |        |
|             | 490)** |        |        | 490)** |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
|             | *      | **%**  | **KM   | *      | **%**  | **KM   |
|             | *n/N** |        | %**    | *n/N** |        | %**    |
+-------------+--------+--------+--------+--------+--------+--------+
| **Schi      |        |        |        |        |        |        |
| zophrenia** |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Type 1      | 51/300 | 17.0%  | 19.5%  | 82/309 | 26.5%  | 29.3%  |
+-------------+--------+--------+--------+--------+--------+--------+
| Type 2      | 67/300 | 22.3%  | 25.9%  | 98/309 | 31.7%  | 35.1%  |
+-------------+--------+--------+--------+--------+--------+--------+
| **Schi      |        |        |        |        |        |        |
| zoaffective |        |        |        |        |        |        |
| Disorder**  |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Type 1      | 51/190 | 26.8%  | 31.0%  | 59/181 | 32.6%  | 37.2%  |
+-------------+--------+--------+--------+--------+--------+--------+
| Type 2      | 53/190 | 27.8%  | 32.1%  | 63/181 | 34.8%  | 39.5%  |
+-------------+--------+--------+--------+--------+--------+--------+

The sponsor repeated the WLW analysis for each of the two diagnostic
subgroups. The results are presented in **Appendix VI-17**.

For patients with schizophrenia, the results were consistent with those
for the entire study population. The combined estimate of treatment
effect favored Clozaril over Zyprexa to a statistically significant
degree (p=0.0298). For Type 1 events, the Clozaril effect was superior
(p=0.0251) and, for Type 2 events, borderline superior (p=0.0516). The
hazard ratios (95% CI's) were 0.67 (0.47, 0.95) and 0.73 (0.54, 1.00),
respectively.

For patients with schizoaffective disorder, the estimates of treatment
effect using the WLW analysis and for Type 1 and Type 2 events
separately favored Clozaril but were smaller than in the schizophrenia
subgroup; none approached statistical significance. The hazard ratios
(95% CI's) for Type 1 and Type 2 events were 0.87 (0.60, 1.27) and 0.85
(0.59, 1.23), respectively.

These data suggest that Clozaril may be less effective in reducing
suicide risk in patients with schizoaffective disorder compared to
patients with schizophrenia.

[Geographic Subgroup Analysis]{.underline}

The sponsor repeated the WLW analysis of time to Type 1 and Type 2
events based on geographic subgroups (U.S. and Canada (N. America) vs.
the rest of the world). The results are summarized in **Appendix
VI-18**. In both subgroups, Clozaril was numerically superior to Zyprexa
in the combined estimate of treatment effect as well as for Type 1 and
Type 2 events separately. However, statistical superiority was not
demonstrated for any comparison in either subgroup. Hazard ratios (95%
CI's) were not substantially different between North America and the
rest of the world (for Type 1 events, 0.78 (0.56, 1.08) and 0.72 (0.48,
1.08), respectively; for Type 2 events, 0.75 (0.55, 1.04) and 0.81
(0.57, 1.16), respectively).

**3. Size of Treatment Effect**

In terms of the anti-suicide effect size in study ABA 451, it is useful
to consider the cumulative probability of a Type 1 event from the
Kaplan-Meier survival analysis.

At week 104, there was a substantial cumulative probability of suicide,
attempted suicide, or hospitalization or increased surveillance due to
imminent suicide risk in both the Clozaril and Zyprexa treatment groups
(0.24 and 0.32, respectively). The 95% CI for the difference between the
two groups is (0.02, 0.15). Thus, the point estimate for the difference
in cumulative probabilities is not large (0.08) and the true difference
may be quite small (0.02).

**4. Choice of Dose**

The sponsor is recommending that the dosage of Clozaril for the
treatment of schizophrenic and schizoaffective disorder patients at risk
for suicide be the same as for patients with treatment-resistant
schizophrenia.

Presumably, in study ABA 451, doses were titrated primarily on the basis
of tolerability and antipsychotic efficacy, as opposed to antisuicidal
efficacy, since most patients did not manifest imminent suicidality most
of the time. Based on this assumption, the sponsor's dosing
recommendations seem appropriate.

**5. Duration of Treatment**

This application seeks an indication for suicidal antipsychotic-naive
patients to initiate continuous antipsychotic treatment with Clozaril or
for suicidal patients currently treated with another antipsychotic to
begin continuous Clozaril therapy either in place of or in addition to
their existing treatment.

In this context, the duration of treatment with Clozaril would be
dictated by its use as an antipsychotic agent and currently labeled
advice would apply.

**D. Summary of Pertinent Published Literature**

**1. Botsis AJ, et al. Clozapine efficacy on suicidal behavior across
two main psychiatric disorders. Eur Neuropsychopharmacol 1997;7:S202.**

This was a prospective study of 10 patients with severe suicidal
behavior, 6 diagnosed with schizophrenia and 4 with psychotic
depression. These patients had received high doses of typical
neuroleptics (and high doses of antidepressants in the depressed
patients) for at least 4 weeks, followed by treatment with clozapine (up
to 450 mg/day) for 4 weeks. Suicidal behavior and general
psychopathology was found to be decreased after 3 weeks of clozapine
therapy.

This study was a small, historical control trial. Details of suicidality
assessments and findings were not provided.

**2. Ciapparelli A, et al. Clozapine for treatment-refractory
schizophrenia, schizoaffective disorder and psychotic bipolar disorder:
a 24-month naturalistic study. J Clin Psychiatry 2000;61:329-334.**

This was a prospective study in adult patients with schizophrenia
(N=31), schizoaffective disorder (N=26), and psychotic bipolar disorder
(N=34). About 25% had suicidal ideation or a history of suicide attempt
at baseline. Patients were treated for 24 months with flexible dose
clozapine; many patients also received other neuroleptics as well as
typical neuroleptics, antidepressants, anticonvulsants, lithium,
benzodiazepines, and other medications. An analysis restricted to those
with suicidal ideation at baseline revealed a significant reduction in
the BPRS-Expanded suicide item at 24 months.

This trial was a historical control trial with efficacy findings
confounded by substantial use of concomitant psychotropic medication.

**3. Littrell KH, et al. The experience of hope in adults with
schizophrenia. Psychiatric Rehabilitation Journal 1996;19:61-65.**

This was a prospective study of the combined effect of psychosocial
treatment and clozapine in 44 adult patients with refractory
schizophrenia. The primary study focus was on 14 patients with previous
suicide attempts. Patients were assessed after 6 and 12 months of
clozapine at a mean dose of 550 mg/day. None of the patients attempted
suicide during the 12 month trial period. The authors suggest that
combined intervention is associated with decreased suicidality.

This was a historical control trial in a small number of patients with
past suicide attempts. Clozapine effects may have been confounded by
psychosocial treatment. The methodology for assessing a reduction in
suicide potential was not described in detail.

**4. Meltzer HY and Okayli G. Reduction of suicidality during clozapine
treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit
assessment. Am J Psychiatry 1995;152:183-190.**

This was a retrospective study that included an evaluation of the effect
of clozapine on suicidality in 183 patients with neuroleptic-resistant
schizophrenia or schizoaffective disorder. Clozapine was begun during an
index hospitalization and 88 neuroleptic-resistant patients received
clozapine for at least 6 months for a period up to 2 years. Data
reflecting suicidal thoughts and suicide attempts prior to clozapine
were compared with corresponding measures during clozapine treatment.
Results indicated a reduction in suicide attempts from 25% (22/88)
pre-clozapine to 3.5% (3/88) after clozapine treatment.

This was a historical control study. Also, although the reduction in the
proportion of patients attempting suicide was remarkable, it was not
clear that the authors had adequately controlled for the durations of
observation during the pre-clozapine and clozapine treatment periods in
analyzing the suicidality results, rendering the findings difficult to
interpret.

**5. Modaj I, et al. Sudden death in patients receiving clozapine
treatment: a preliminary investigation. J Clin Psychopharmacology
2000;20:325-327.**

This retrospective study examined rates of sudden death, suicide, and
deaths secondary to known diseases in schizophrenic patients from a
mental health center database over a period of 6 years, 8 months. This
encompassed 561 patients treated with clozapine and 4918 patients
treated with other drugs. Among clozapine patients, 1.07% experienced
sudden death compared to 0.28% of non-clozapine patients (p\<0.01). A
greater proportion of non-clozapine patients died secondary to known
diseases (1.75% vs. 0.35%, p\<0.05). The fractions of patients who
suicided were not significantly different between clozapine and
non-clozapine patients (0.36% vs. 0.10%, respectively).

The two treatment groups were not randomized and it does not appear that
the authors controlled for duration of exposure or other potentially
confounding variables.

**6. Munro J, et al. Active monitoring of 12,760 clozapine recipients in
the U.K. and Ireland. Br J Psychiatry 1999;175:576-580.**

Data from 12,760 patients who were registered to receive clozapine in
the U.K. and Ireland (Clozaril Patient Monitoring Service or CPMS) were
retrospectively analyzed to identify risk factors for agranulocytosis.
Of 144 deaths, 13 were noted to be confirmed suicides. Based on a review
of the literature, the suicide rate among schizophrenic patients in
various cited studies was consistently about 20 times greater than that
in the general population. However, the suicide rate in this CPMS cohort
was only about 5 times higher than that expected for the U.K.
population, suggesting that clozapine may have an anti-suicide effect.

This was an observational study that used literature-reported estimates
of suicide risk as a comparator. This trial did not control for the
possible effects of regular clinical contact for WBC monitoring on
suicide risk. Also, the adequacy of ascertainment of deaths due to
suicide is difficult to gauge.

**7. Reid WH, et al. Suicide prevention effects associated with
clozapine therapy in schizophrenia and schizoaffective disorder.
Psychiatric Services 1998;49:1029-1033.**

This was a retrospective analysis of annual suicide rates among patients
who received services from the Texas Department of Mental Health and
Mental Retardation. A total of 30,130 patients with schizophrenia and
schizoaffective disorder were treated over a two year period
(1993-1995). In this population, the average annual suicide rate was
63.1 per 100,000 patients. During a 6 year interval (1991-1996), 1,367
patients received clozapine with only one suicide in this group,
yielding an annual rate of 12.74 per 100,000 patients (95% CI 0-53 per
100,000).

This study did not compare randomized groups. Also, it did not control
for regular contact associated with WBC monitoring and did not adjust
for duration of drug exposure.

**8. Sajatovic M, et al. An assessment of clinical practice of clozapine
therapy for veterans. Psychiatric Services 2000;51:669-671.**

This was a retrospective study of 2,996 patients with schizophrenia
treated with clozapine in the U.S. Department of Veterans Affairs
healthcare system over a 5 year period (1991-1996). Prior to treatment,
42.3% of patients has a history of suicide attempts. Also, 5% attempted
suicide and 17.5% had suicidal ideation in the month prior to starting
clozapine. During the study observation period, 2 patients (0.1%) died
due to suicide.

This study suffers several weaknesses, to include lack of an adequately
defined control group, no adjustment for duration of drug exposure,
apparent comparison of disparate measures of suicidality (attempts and
ideation pre-clozapine versus suicide deaths on clozapine), lack of
control for the potential effect of regular patient contact, and
possibly inadequate ascertainment of suicide deaths.

**9. Sernyak MJ, et al. Impact of clozapine on completed suicide. Am J
Psychiatry 2001;158:931-937.**

This study examined the discharge summaries of 45,917 unique patients
with Veterans Affairs (VA) psychiatric hospitalizations of at least one
day for the fiscal years 1992 through 1995 in which the primary
discharge diagnosis was schizophrenia. From this group, 1,415 patients
were identified who started clozapine treatment for the first time
during an "index" hospitalization. Then, using a matching process, a
two-fold larger (N=2,830) group of control subjects who had not received
clozapine during the study period were identified from the remaining
discharged patients. Utilizing the National Death Index (NDI), searches
were conducted for any study patients who died beginning with the year
of discharge and continuing through every subsequent year through the
end of 1998. Then, a coding algorithm from the National Center for
Health Statistics was used to determine the most probable primary cause
of death. The primary clozapine group comprised patients who received
clozapine for any length of time. Follow-up time for each individual was
calculated as the time between hospital discharge until either the date
of death or December 31, 1998. The total follow-up time in each group
was used to compute all-cause mortality and cause-specific mortality
rates. The duration of clozapine treatment for each patient was
determined using data from the VA's National Clozapine Coordinating
Center database. In total, 345 deaths were identified, 250 in the
control group and 95 in the clozapine group. Among the deaths that were
ruled suicide, 10 occurred in the clozapine group and 23 occurred in the
control group. The rate of suicide in the total clozapine group was
slightly less than that in the control group but not significantly so
(1.50 versus 1.75 per 1,000 person-years; p=0.76).

Although this study is more rigorously designed than most previously
published studies in this area, it too has flaws. Most importantly, the
matching process did not include some factors that might contribute
substantially to suicide risk, such as previous suicide attempts and
depressive symptomatology. Thus, it is difficult to feel assured that
the clozapine and control groups were balanced on important risk factors
for suicidality. In addition, it appears that the calculation of
follow-up time for clozapine patients may have included time during
which the patient did not receive clozapine treatment. If true, this
means that the patient exposure time counted under the clozapine group
may in fact be inflated and the true rate of suicide in the clozapine
group may be considerably higher than computed. This is a potential
major confounding factor that does not seem to be addressed in the
paper.

**10. Spivak B, et al. Diminished suicidal and aggressive behavior, high
plasma norepinephrine levels, and serum triglyceride levels in chronic
neuroleptic-resistant schizophrenic patients maintained on clozapine.
Clin Neuropharmacol 1998;21:245-250.**

This study evaluated the effects of clozapine on multiple variables,
including a retrospective analysis of suicidality, in a group of 30
neuroleptic-resistant chronic schizophrenic patients who were treated
with clozapine and a control group of 20 chronic schizophrenic patients
maintained on a typical antipsychotic for a one year study period. Past
suicide attempts were reported in 7/30 clozapine patients and in 11/20
control patients. None of the clozapine patients attempted suicide
during the study period compared to 5 patients in the control group;
this difference was statistically significant (p\<0.05).

This is a small study comparing non-randomized groups. There was a
numerical difference in the fraction of patients with past suicide
attempts between the two groups (7/30 or 23% of clozapine patients
versus 11/20 or 55% of the control group), a possible indicator that the
control group may have been more prone to suicide attempts. This study
also did not control for the possible effects of regular clinical
contact associated with WBC monitoring in clozapine patients.

**11. Walker AM, et al. Mortality in current and former users of
clozapine. Epidemiology 8;1997:671-677.**

This retrospective study of mortality among clozapine-treated patients
was based on a cohort of patients in the U.S. Clozaril National Registry
(CNR) during the period of April 1, 1991 to December 31, 1993. For each
patient, the observation period started with April 1, 1991 or the
earliest WBC record in the CNR for patients who began Clozaril after
that date. The observation period ended with December 31, 1993, the date
on which the patient reached age 101, or the date of death, whichever
came first. Then, for each patient, each day during the observation
period was classified as current use, recent use (up to and including 3
months after stopping Clozaril), or past use (more than 3 months after
stopping Clozaril).

Deaths among this cohort were ascertained using the National Death Index
(NDI) and the Social Security Administration Death Master Files using
certain matching criteria. Death certificates were then requested from
the states and the underlying causes of death were coded in accordance
with ICD-9, along with recording of autopsy data. Mortality rates
(standardized for age, race, and gender) in current and recent use were
compared with rates in past use. The primary analysis focused on
patients in the age range 10 to 54 years.

A total of 57,681 patients were eligible for the primary study cohort,
representing a total of 85,399 person-years (PY) of observation. There
were 396 deaths in this cohort. With respect to deaths due to suicide,
the standardized mortality ratios (95% CI), using past use for
comparison, were 0.17 (95% CI = 0.10-0.30) for current use and 1.11
(0.62-1.99) for recent use. These data suggest that active clozapine
treatment is associated with a reduced risk of suicide.

The finding of a reduced suicide rate during the current use period is
difficult to interpret with confidence. These were not randomized
samples and it is unknown whether the use periods were balanced for
various factors that might contribute to suicide risk. Also, as
suggested by the authors, discontinuation of Clozaril due to poor
response may select out a subset of patients particularly vulnerable to
suicide, shifting these patients to the recent and past use categories.
And, as with other studies, the WBC monitoring program may itself
produce a bias by reducing the risk of suicidality through regular
contact with healthcare staff or by earlier detection of the emergence
of suicidality compared to patients in the recent and past use
categories.

**E. Assessment of Efficacy Data Quality**

A total of 21 CRF's were randomly selected by the undersigned to audit
the quality of data pertinent to suicidality from study ABA 451. Of
these, 7 were for patients who were identified by the sponsor as not
having experienced a Type 1 or Type 2 Event and 14 were identified as
having experienced one of these events. The selected samples represent
about 1% of the 700 patients not having an event and about 5% of the 280
patients having an event. All 21 patients selected for audit are listed
in **Appendix VI-19**.

The primary goal of this audit was to verify that patients were
appropriately classified with respect to suicidality based on clinical
documentation in the CRF's. For patients with multiple Type 1 Events,
this review focused on the first such event. Clinical data from the CRF
forms listed in **Appendix VI-20** were examined.

This audit revealed only one finding that was present for 3 of the
patients classified as having a Type 1 Event (Zyprexa patient 102-0012,
Clozaril patient 127-0007, and Zyprexa patient 201-0004). In each of
these 3 cases, the blinded psychiatrist indicated the absence of a Type
1 Event on a particular date whereas the Suicide Monitoring Board (SMB)
found that a Type 1 Event had occurred on that date. Curiously, in each
case, one of the SMB members initially voted that no event had occurred
but subsequently changed to indicate the presence of a Type 1 Event.

To evaluate these discrepancies, I examined clinical documentation
provided by the Principal Investigators regarding these events (mainly
the "Imminent Risk of Suicide Requiring Hospitalization" and "Suicide
Attempt" forms). In each case, I found that the evidence in support of a
Type 1 Event was weak. For example, the Principal Investigator indicated
a low risk of self-injury for 2 patients who were hospitalized "for
imminent risk of suicide." In the third patient, the Principal
Investigator clearly indicated that an attention-getting suicide gesture
of low risk had occurred although the SMB later determined that this was
a suicide attempt. While the accuracy of the SMB determinations is
arguable, it is notable that all 3 cases involved a possible error in
designating a non-suicidal event as a suicidal-event; I detected no
cases where the SMB had made a possible error in the reverse direction.

To better assess this potential source of bias, it is recommended that
all SMB documentation (e.g., conference minutes) related to these 3
patients be requested to better assess the determinations made. If that
assessment is not reassuring, it is further recommended that relevant
CRF forms for all remaining patients for whom there was a discrepancy
between the SMB and the blinded psychiatrist be requested from the
sponsor and examined. Finally, if that examination reveals a large
number of cases with questionable SMB determinations, a reanalysis of
the primary efficacy variables excluding these cases is recommended.

An additional audit searched for documentation indicating that the
blinded psychiatrist had become unblinded during study ABA 451. Each
blinded psychiatrist had the opportunity at each CGI-SS assessment of
indicating in the CRF whether they had become unblinded to the patient's
treatment. The relevant CRT (CGI002.xpt) was searched for any
investigators who indicated unblinding at any visit. This search
revealed 6 blinded psychiatrists at 6 different sites who indicated that
they had become unblinded to the treatment of the following patients:
110-0001, 117-0001, 119-0002, 122-0006, 131-0005, and 701-0001. The ways
in which unblinding occurred were not indicated. The sponsor should be
requested to determine, to the extent possible, how these breaches
occurred so that the adequacy of blinding in this trial can be more
fully evaluated.

In summary, an audit of the suicidality data revealed two potential
findings (possible biased SMB determinations and unblinding) that could
impact on the reliability of these data. These findings should be
further investigated, as recommended above.

**F. Conclusions Regarding Efficacy**

The findings of study ABA 451 cannot support the approval of Clozaril
for the treatment of suicidality in patients with schizophrenia and
schizoaffective disorder, as proposed by the sponsor (see the discussion
in section VI.C.1 above).

Nonetheless, this study is capable, by design, of demonstrating a
reduced risk of suicidality associated with long-term Clozaril treatment
compared to long-term Zyprexa treatment. In this regard, the study
results are considered inconclusive at this time given a number of
irregularities in the conduct and analysis of this trial, which are
discussed in section VI.B.12 above.

The published studies reviewed above suggest, on the whole, that
Clozaril may be associated with a reduced risk of suicide compared to
other treatments. However, each study suffers flaws which preclude any
convincing demonstration of such an effect.

**VII. Integrated Review of Safety**

**A. Methodology of the Safety Review**

Clozaril has been marketed in the U.S. and abroad for several years and
the safety profile of Clozaril has been extensively evaluated. Thus, the
examination of safety in this review was limited to an assessment of the
more serious adverse events observed in study ABA 451, namely: 1)
deaths, 2) non-fatal serious adverse events, and 3) adverse events that
led to premature termination from the study.

The safety population for study ABA 451 was defined as all randomized
patients who took at least one dose of study medication (479
Clozaril-treated patients and 477 Zyprexa-treated patients). The last
patient completed this trial on 2-14-01.

For patients who dropped out, the investigator was to maintain regular
contact with the patient or family member every 12 weeks up to the time
that would have been study week 104 for that patient (i.e., for the
remainder of the 2 year observation period).

**B. Safety Findings**

**1. Deaths**

A total of 22 patients died during the 2 year observation period or
within 30 days of discontinuing study medication: 13 Clozaril patients
and 9 Zyprexa patients. Thus, the crude all-cause mortality rate was
2.7% (13/479) for Clozaril and 1.9% (9/477) for Zyprexa. These rates are
not significantly different (p=0.39; Mantel-Haenszel Chi-Square).

I reviewed the Narrative Summary for each patient who died. **Appendix
VII-1** is a line listing of all 22 deaths with the cause of death as
determined by my review.

Among the 13 Clozaril patient deaths, 2 occurred more than 30 days after
discontinuing treatment and were unlikely to be related to Clozaril
treatment (patients 122-0010 and 802-0012). Among the remaining 11
Clozaril deaths, 4 were the result of suicide or complications of a
suicide attempt and there was one death each due to pulmonary embolism,
overdose, cancer, and cardiac arrest. In 3 cases, the cause of death
could not be determined with reasonable certainty.

**2. All Serious Adverse Events**

The protocol for study ABA 451 defined serious adverse events (SAE's) as
those which meet any of the following criteria:

• fatal or life-threatening.

• requires or prolongs hospitalization.

• significantly or permanently disabling or incapacitating.

• cancer, congenital anomaly, or birth defect.

• resulting from an overdose.

All SAE's occurring after signing informed consent until 28 days after
stopping study drug were reported.

In the Clozaril group, 48.2% (231/479) of the patients experienced an
adverse event classified as serious compared to 49.3% (235/477) of the
Zyprexa patients. Appendix 7.2, Listing 10.2-1, of the report for study
ABA 451 contains a line listing by patient of all patients who
experienced an SAE. An enumeration by treatment group of all SAE's (by
MedDRA preferred term) experienced by at least one Clozaril-treated
patient is provided in **Appendix VII-2** of this review.

I reviewed the Narrative Summaries for a number of patients with SAE's
to obtain further clinical information about the nature and
circumstances of the events. The Narrative Summaries reviewed are listed
in **Appendix VII-3**. Also, this information was supplemented in many
cases by data from the Case Report Tabulations.

Based on a consideration of the above clinical data, I considered the
following events reasonably attributable to Clozaril treatment: bowel
obstruction, WBC's decreased, hyperglycemia, dizziness, and somnolence.
These events will be discussed in **section VII.E** below.

**3. Dropouts due to Adverse Events**

In the Clozaril treatment group, 8.6% (41/479) of the patients
prematurely discontinued treatment due to an adverse event compared to
6.9% (33/477) of the Zyprexa patients. The adverse experiences most
commonly leading to dropout in the Clozaril group were WBC's decreased
(1.7% of Clozaril and 0.0% of Zyprexa patients) and somnolence (1.0% of
Clozaril and 0.2% of Zyprexa patients).

A line listing of all patients who dropped out due to an adverse event
may be found in Appendix 7.1, Listing 10.1-2, of the study report for
ABA 451. An enumeration of the Clozaril patients who discontinued
treatment due to specific adverse events is provided in **Appendix
VII-4** of this review.

My examination of the events leading to dropout among the
Clozaril-treated patients revealed no clinically important events which
I considered attributable to Clozaril beyond those events identified in
the above review of SAE's.

**C. Adequacy of Patient Exposure and Safety Assessments**

Clozaril has been marketed for over a decade for use in patients with
schizophrenia. This supplement seeks to add patients with
schizoaffective disorder to the target population. There were only 190
patients with schizoaffective disorder randomized to Clozaril in study
ABA 451. Although this exposure is small, there is no known reason not
to extrapolate the primary safety experience in schizophrenic patients
to the schizoaffective disorder population. Thus, this limited exposure
should not preclude the approval of this supplement.

The safety assessments in study ABA 451 are considered adequate to
detect frequently occurring major toxicities associated with extended
Clozaril use in the study population. However, one deficiency was the
lack of some routine safety assessments which may have yielded useful
long-term data, such as fasting blood glucose levels, cholesterol and
triglyceride levels, and ECG's.

**D. Safety Data Quality and Completeness**

Approximately 5% of the 68 Case Report Forms (CRF's) submitted for
patients in study ABA 451 who died or experienced other designated
serious adverse events were audited by the undersigned. This audit
consisted of an examination of the consistency of adverse event
information across the CRF, Narrative Summary, and Case Report
Tabulation (CRT) adverse event line listing (AEV001.xpt) for four
randomly selected patients (patients 117-0004, 120-0014, 301-0003, and
502-0008). This audit revealed no important discrepancies.

The appropriateness of the coding of reported adverse event terms to
MedDRA preferred terminology for patients in study ABA 451 was evaluated
by the undersigned. This consisted of an examination of the CRT adverse
event line listing, sorted by preferred term and also by reported
(verbatim) term. This examination revealed no errors in adverse event
coding.

In terms of data completeness, two deficiencies were noted:

• safety findings discovered by non-trial healthcare providers and
facilities were often missing.

• follow-up information on abnormalities observed during the trial was
often not available, making evaluation of the outcome of these events
impossible.

Given the wealth of postmarketing safety data available for Clozaril,
these deficiencies should not preclude approval of this supplement.

**E.** **Summary of Important Drug-Related Safety Findings**

**1. WBC Count Decreased**

Eight Clozaril (1.7%) and no Zyprexa patients experienced decreases in
white blood cell (WBC) counts that were classified as serious (p=0.005,
MH Chi-Square). Six of these patients dropped out for this reason. None
of these patients experienced sepsis, a total WBC count under 1,000/cmm,
or an absolute neutrophil count under 500/cmm. The lowest counts were
observed in patient 701-0025, who experienced a decrease in total WBC's
from 5,900 to 1,700/cmm and in neutrophils from 3,500 to 650/cmm. No
follow-up counts were available for this patient.

In terms of the proportions of patients who had a total WBC count
≤2,800/cmm at any point during the trial, 1.3% (6/474) of the Clozaril
and 0.6% (3/474) of the Zyprexa patients met this criterion (p=0.32, MH
Chi-Square).

No cases of agranulocytosis or aplastic anemia were reported.

Leukopenia is a well-known effect of Clozaril and is the reason Clozaril
is available only through a controlled distribution system. Clozaril is
considered to be adequately labeled for this adverse event.

**2. Bowel Obstruction**

In study ABA 451, three Clozaril patients experienced bowel obstructions
consistent with paralytic ileus. One of these patients (129-0010)
experienced two episodes of obstruction during Clozaril treatment, the
last leading to treatment discontinuation. Another patient (301-0019)
underwent surgery for a perforated appendix about 2 weeks prior to
symptoms of obstruction. Clozaril was stopped, with recovery of bowel
function 8 days later. The third patient (302-0010) had a grossly
distended transverse colon and evidence of renal impairment due to
dehydration. Clozaril was stopped but he experienced a cardiac arrest of
uncertain etiology 2 days later and died. Obstruction in all of these
patients resulted in hospitalization and intervention.

Only one Zyprexa-treated patient experienced a bowel obstruction.

Constipation was reported by 25.1% (120/479) of Clozaril patients; 48 of
these events were rated as moderate or severe. In the Zyprexa group,
9.6% (46/477) of the patients reported constipation. The difference
between the groups was highly statistically significant (p\<0.001,
Mantel-Haenszel Chi-Square).

These events are probably related to the potent anticholinergic effects
of Clozaril, which are described in current labeling under
PRECAUTIONS/Anticholinergic Toxicity.

**3. Hyperglycemia**

At least one treatment-emergent adverse event suggesting a problem with
glucose regulation was reported in 4.8% (23/479) of the Clozaril and
5.5% (26/477) of the Zyprexa patients in study ABA 451. These events had
been coded to one of the following MedDRA preferred terms: hyperglycemia
NOS, diabetes mellitus NOS, ketoacidosis, blood glucose increased,
glucose tolerance decreased, and glycosuria.

Plasma glucose levels were not routinely assessed during this study.
Thus, a more systematic evaluation of glucose dysregulation is not
possible.

There have been a number of spontaneous adverse event reports as well as
literature reports documenting problems with glucose regulation during
treatment with either Clozaril and Zyprexa.[^21] The above data are
consistent with the possibility that hyperglycemia and diabetes may be
causally linked to these agents although such a relationship has not
been convincingly demonstrated. Current Clozaril labeling contains a
statement under PRECAUTIONS/Hyperglycemia that adequately advises
prescribers of this possible relationship.

**4. Dizziness**

Non-vertiginous dizziness was reported as an adverse event in 26.9%
(129/479) of the Clozaril group and 12.4% (59/477) of the Zyprexa group
in study ABA 451; this difference is highly significant (p\<0.001, MH
Chi-Square). Events coded to this MedDRA term included dizziness,
lightheadedness, and feeling faint. Four Clozaril patients and no
Zyprexa patients dropped out due to this adverse experience.

An etiologic explanation for this event is not clear.

According to the ADVERSE REACTIONS section of Clozaril labeling,
dizziness, to include vertigo, was reported in 19% of Clozaril patients
in premarketing clinical trials (N=842). Given that these trials were
probably much shorter than study ABA 451, the above finding is
considered to be consistent with the figure cited in labeling.

**5. Somnolence**

Somnolence was reported as a treatment-emergent adverse experience in
45.9% (220/479) of Clozaril and 24.7% (118/477) of Zyprexa patients in
ABA 451. This difference is highly statistically significant (p\<0.001,
MH Chi-Square). This MedDRA preferred term subsumed reported events
including drowsiness, sedation, and sleepiness. Five Clozaril patients
and one Zyprexa patient dropped out due to this adverse event.

This finding is felt to be consistent with information in the ADVERSE
REACTIONS section of Clozaril labeling, which describes drowsiness or
sedation in 39% of Clozaril-treated patients in premarketing clinical
trials.

**F. Safety Conclusions**

This limited review of safety data from study ABA 451 revealed no
previously unrecognized toxicities associated with Clozaril which would
preclude the approval of this supplement or require amendment of
Clozaril labeling.

**VIII. Dosing, Regimen, and Administration Issues**

The dosing scheme utilized in study ABA 451 is consistent with that
currently labeled for the treatment of patients with refractory
schizophrenia. If the sponsor elects to pursue approval of a claim for
the reduction of suicide risk with long-term therapy, this dosing
regimen would be appropriate. However, before approval for this use, it
will be critical to decide whether to grant approval as a new indication
(as opposed to simply describing the study in labeling under Clinical
Trials) and, if so, to delineate in labeling an appropriate target
population.

**IX. Use in Special Populations**

Neither gender nor age group were significant predictors of time to a
Type 1 or time to a Type 2 event in covariate analyses using a full Cox
proportional hazards regression model. Race was not examined as an
explanatory variable in these analyses.

**X. Review of Proposed Labeling**

Since it is recommended that this supplement not be approved, the
sponsor's proposed labeling will not be discussed in this review.

**XI. Conclusions and Recommendations**

It is recommended that the claim for the use of Clozaril to treat
suicidality not be approved. Study ABA 451 was not designed to assess
the efficacy of Clozaril in the treatment of suicidality.

If Novartis elects to pursue approval of Clozaril as a long-term measure
to reduce the risk of suicidality, it is recommended that the sponsor
address the following concerns regarding study ABA 451:

1\) Apparently a total of 72 study patients were lost to follow-up.
Further efforts should be made to ascertain whether the 33 Clozaril and
39 Zyprexa patients who were lost to follow-up committed suicide,
attempted suicide, or were hospitalized or placed under increased
surveillance due to imminent suicide risk around the time of study
discontinuation.

2\) The primary efficacy analysis, using the method of Wei, Lin, and
Weissfeld, is described as including Type 1 and Type 2 events regardless
of whether the patient was taking study medication at the time of the
event. This makes attribution of event occurrence or non-occurrence to
drug very tenuous in this long-term trial. Additionally, Amendment #9 to
the study protocol allowed patients who had dropped out of the study to
later return to full study participation. This is may have introduced a
confounding influence of suicide risk in this trial. Therefore, the
primary efficacy analysis should be repeated after right-censoring
patients who discontinued study drug, even if those patients later
re-entered the study as full participants. Also, this analysis should
incorporate any and all new information on the 72 patients who were
reported as lost to follow-up (see item 1 above).

3\) An audit of suicidality information, including Case Report Forms, on
a small sample of study patients revealed three cases in which the SMB
determinations are questionable. To permit a more complete understanding
of how these determinations were made, all SMB documentation, to include
SMB conference minutes, related to the following three patients should
be submitted for Agency examination: 102-0012, 127-0007, and 201-0004.

4\) It is noted that six Blinded Psychiatrists acknowledged becoming
unblinded during the study. These individuals performed CGI-SS-BP
ratings on the following study patients: 110-0001, 117-0001, 119-0002,
122-0006,

131-0005, and 701-0001. These instances of unblinding should be
investigated to determine how these breaches occurred. The explanations
should be provided for our review so that the adequacy of blinding in
the trial can be more fully evaluated.

Furthermore, if the sponsor amends this application to pursue the
suicidality prevention claim, it may be helpful for the Division to
obtain the advice of the Psychopharmacological Drugs Advisory Committee
with respect to the following questions:

1\) Does study ABA 451 provide adequate evidence to support a claim of
reduction in the risk of suicidality? The response should include a
consideration of the following:

a\) The difference between Clozaril and Zyprexa was not very large. For
example, at the end of two years, the cumulative probability of a Type 1
event was 0.24 for Clozaril and 0.32 for Zyprexa, with a 95% confidence
interval for the intergroup difference being 0.02 to 0.14.

b\) Unlike most claims for psychiatric conditions, this would be based
on a single study against a single comparator agent. While published
studies do provide evidence suggesting a reduction in suicide risk, none
are of such quality that they are capable of providing data that would
truly replicate the findings of ABA 451.

c\) A large proportion of patients in this trial took concomitant
medication that could confound assessment of suicide risk, such as
antipsychotics and antidepressants. It would admittedly be virtually
impossible to entirely rule out a differential confounding influence
that might bias the study results and, to some extent, the sponsor's
analysis of such use might be considered reassuring. Nonetheless, there
is a need to reasonably judge whether this treatment was so extensive
that it significantly degraded the scientific credibility of this trial.

d\) For over 40% of the patients in each treatment group, there was a
change in the Blinded Psychiatrist who rated the change in the patient's
suicidality at each visit relative to the patient's baseline condition.
This was a key outcome measure. The reliability of a new rater in
assessing change from the baseline condition is questionable.

2\) If the answer to the above question is affirmative, what guidance
should be provided in labeling to assist prescribers in selecting
patients for Clozaril therapy under this claim?

Gregory M. Dubitsky, M.D.

August 1, 2002

cc: NDA 19-758

HFD-120/Division File

HFD-120/GDubitsky

/TLaughren

/SHardeman

**SECTION XII:**

**APPENDICES**

**APPENDIX IV-1**

**STUDY ABA 451**

**BASELINE DEMOGRAPHIC CHARACTERISTICS**

**(ALL RANDOMIZED PATIENTS)**

![](media/image1.png){width="5.697916666666667in"
height="5.208333333333333in"}

**APPENDIX IV-2**

**STUDY ABA 451**

**OVERALL EXPOSURE BY TREATMENT DURATION**

**(SAFETY POPULATION)**

![](media/image2.png){width="5.997222222222222in"
height="3.0083333333333333in"}

+---------------------+------------------------------------------------+
| **appendix v-1**    |                                                |
|                     |                                                |
| **items reviewed**  |                                                |
+---------------------+------------------------------------------------+
| **Submission Date** | **Item Description**                           |
+---------------------+------------------------------------------------+
| 2-28-02             | [Volume 1]{.underline}                         |
|                     |                                                |
|                     | Proposed labeling                              |
|                     |                                                |
|                     | Debarment certification                        |
|                     |                                                |
|                     | Financial disclosure information               |
|                     |                                                |
|                     | [Volume 4]{.underline}                         |
|                     |                                                |
|                     | Published literature reports                   |
|                     |                                                |
|                     | [Electronic Format]{.underline}                |
|                     |                                                |
|                     | Study report: ABA 451                          |
|                     |                                                |
|                     | Case Report Tabulations: ABA 451               |
|                     |                                                |
|                     | Case Report Forms: ABA 451                     |
+---------------------+------------------------------------------------+
| 3-29-02             | Median dose by visit data                      |
|                     |                                                |
|                     | Diagnostic subgroup efficacy analysis          |
+---------------------+------------------------------------------------+
| 5-17-02             | Correction to ABA 451 Study Report             |
+---------------------+------------------------------------------------+
| 6-24-02             | Analysis of concomitant medication             |
+---------------------+------------------------------------------------+

+-----------------------------------------------------------------------+
| **appendix v-2:**                                                     |
|                                                                       |
| **selected serious adverse events**                                   |
+-----------------------------------------------------------------------+
| Myocardial infarction                                                 |
|                                                                       |
| Pericarditis NOS                                                      |
|                                                                       |
| Appendicitis perforated                                               |
|                                                                       |
| Hematemesis                                                           |
|                                                                       |
| Intestinal obstruction NOS                                            |
|                                                                       |
| Pancreatitis NOS                                                      |
|                                                                       |
| Neuroleptic malignant syndrome                                        |
|                                                                       |
| Hepatic disorder NOS                                                  |
|                                                                       |
| Colitis pseudomembranous                                              |
|                                                                       |
| Accidental overdose (therapeutic agent)                               |
|                                                                       |
| Ketoacidosis                                                          |
|                                                                       |
| Tetany                                                                |
|                                                                       |
| Rhabdomyolysis                                                        |
|                                                                       |
| Paraplegia                                                            |
|                                                                       |
| Intra-uterine death                                                   |
|                                                                       |
| Renal failure NOS                                                     |
|                                                                       |
| Pleural effusion                                                      |
|                                                                       |
| Respiratory distress                                                  |
|                                                                       |
| Respiratory failure (exc neonatal)                                    |
|                                                                       |
| Acute circulatory failure                                             |
|                                                                       |
| Transient ischemic attack                                             |
+-----------------------------------------------------------------------+

+--------+--------+-----------------+--------------------------------+
| **ap   |        |                 |                                |
| pendix |        |                 |                                |
| vi-1** |        |                 |                                |
|        |        |                 |                                |
| *      |        |                 |                                |
| *study |        |                 |                                |
| aba    |        |                 |                                |
| 451**  |        |                 |                                |
|        |        |                 |                                |
| *      |        |                 |                                |
| *study |        |                 |                                |
| sites, |        |                 |                                |
| number |        |                 |                                |
| of     |        |                 |                                |
| pa     |        |                 |                                |
| tients |        |                 |                                |
| enr    |        |                 |                                |
| olled, |        |                 |                                |
| and    |        |                 |                                |
| pri    |        |                 |                                |
| ncipal |        |                 |                                |
| inv    |        |                 |                                |
| estiga |        |                 |                                |
| tors** |        |                 |                                |
+========+========+=================+================================+
| **Ce   | **Loca | **Number        | **Principal Investigator**     |
| nter** | tion** | Enrolled**      |                                |
|        |        |                 |                                |
| **Nu   | *      | **(Cloza        |                                |
| mber** | *(coun | pine/Zyprexa)** |                                |
|        | try)** |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 101    | USA    | 8/9             | H. Edward Logue, M.D.          |
+--------+--------+-----------------+--------------------------------+
| 102    | USA    | 6/7             | Pedro Delgado, M.D.            |
|        |        |                 |                                |
|        |        |                 | Francisco Moreno, M.D.         |
+--------+--------+-----------------+--------------------------------+
| 103    | USA    | 6/5             | Dennis Pavlinac, M.D.          |
+--------+--------+-----------------+--------------------------------+
| 104    | USA    | 10/11           | Mark H. Rapaport, M.D.         |
+--------+--------+-----------------+--------------------------------+
| 105    | USA    | 14/14           | Steven Potkin, M.D.            |
+--------+--------+-----------------+--------------------------------+
| 106    | USA    | 7/8             | David A. Sack, M.D.            |
+--------+--------+-----------------+--------------------------------+
| 107    | USA    | 14/14           | George M. Simpson, M.D.        |
+--------+--------+-----------------+--------------------------------+
| 108    | USA    | 2/2             | Dan L. Zimbroff, M.D.          |
+--------+--------+-----------------+--------------------------------+
| 109    | USA    | 3/2             | Ira D. Glick, M.D.             |
|        |        |                 |                                |
|        |        |                 | Ben H. Flores, M.D.            |
+--------+--------+-----------------+--------------------------------+
| 110    | USA    | 2/1             | Doris Gunderson, M.D.          |
+--------+--------+-----------------+--------------------------------+
| 111    | USA    | 4/4             | Phillip Seibel, M.D.           |
|        |        |                 |                                |
|        |        |                 | Adam Lowy, M.D.                |
+--------+--------+-----------------+--------------------------------+
| 112    | USA    | 9/10            | Carl Eisdorfer, M.D., Ph.D.    |
|        |        |                 |                                |
|        |        |                 | Richard Douyon, M.D.           |
+--------+--------+-----------------+--------------------------------+
| 113    | USA    | 3/ 4            | Michael G. Plopper, M.D.       |
+--------+--------+-----------------+--------------------------------+
| 114    | USA    | 16/16           | James Chou, M.D.               |
|        |        |                 |                                |
|        |        |                 | Jean-Pierre Lindenmayer, M.D.  |
+--------+--------+-----------------+--------------------------------+
| 115    | USA    | 2/2             | Vinod Kumar, M.D.              |
|        |        |                 |                                |
|        |        |                 | Jack Krasuski, M.D.            |
+--------+--------+-----------------+--------------------------------+
| 116    | USA    | 6/6             | Alan I. Green, M.D.            |
+--------+--------+-----------------+--------------------------------+
| 117    | USA    | 8/6             | George Hsu, M.D.               |
+--------+--------+-----------------+--------------------------------+
| 118    | USA    | 3/2             | Oladapo Tomori, M.D.           |
+--------+--------+-----------------+--------------------------------+
| 119    | USA    | 1/1             | Richard Balon, M.D.            |
+--------+--------+-----------------+--------------------------------+
| 120    | USA    | 7/7             | George T. Grossberg, M.D.      |
|        |        |                 |                                |
|        |        |                 | Winston W. Shen, M.D.          |
|        |        |                 |                                |
|        |        |                 | Ricky S. Mofsen, D.O.          |
+--------+--------+-----------------+--------------------------------+
| 122    | USA    | 5/6             | Ronald Centric, D.O.           |
|        |        |                 |                                |
|        |        |                 | Mark W. Viner, M.D.            |
|        |        |                 |                                |
|        |        |                 | Saide Altinsan, M.D.           |
+--------+--------+-----------------+--------------------------------+
| 123    | USA    | 4/4             | Delbert Robinson, M.D.         |
+--------+--------+-----------------+--------------------------------+
| 124    | USA    | 6/7             | Jean-Pierre Lindenmayer, M.D.  |
+--------+--------+-----------------+--------------------------------+
| 125    | USA    | 10/11           | Naveed Iqbal, M.D.             |
+--------+--------+-----------------+--------------------------------+
| 126    | USA    | 9/8             | Jorg J. Pahl, M.D.             |
+--------+--------+-----------------+--------------------------------+
| 127    | USA    | 8/6             | Jeffrey-Lee Peters, M.D.       |
|        |        |                 |                                |
|        |        |                 | Daniel P. VanKammen, M.D.,     |
|        |        |                 | Ph.D.                          |
+--------+--------+-----------------+--------------------------------+
| 128    | USA    | 4/6             | Richard C. Josiassen, Ph.D.    |
+--------+--------+-----------------+--------------------------------+
| 129    | USA    | 7/6             | Herbert Y. Meltzer, M.D.       |
+--------+--------+-----------------+--------------------------------+
| 130    | USA    | 8/8             | Mary Ann Knesevich, M.D.       |
+--------+--------+-----------------+--------------------------------+
| 131    | USA    | 4/5             | Michael Lesem, M.D.            |
|        |        |                 |                                |
|        |        |                 | Vaidyanath Iyer, M.D.          |
+--------+--------+-----------------+--------------------------------+
| 132    | USA    | 2/0             | Richard Greenberg, M.D.        |
+--------+--------+-----------------+--------------------------------+
| 201    | Canada | 6/5             | Guy Chouinard, M.D., Sc. FRCP, |
|        |        |                 | FAPA                           |
+--------+--------+-----------------+--------------------------------+
| 203    | Canada | 4/4             | Siemion Altman, M.D., FRCPC    |
+--------+--------+-----------------+--------------------------------+
| 301    | UK     | 9/9             | Thomas A. Fahy, M.D.           |
+--------+--------+-----------------+--------------------------------+
| 302    | UK     | 25/24           | Prof. Stephen Martin, M.D.     |
+--------+--------+-----------------+--------------------------------+
| 303    | UK     | 13/12           | Sophie Frangou, M.D.           |
+--------+--------+-----------------+--------------------------------+
| 304    | UK     | 7/6             | Prof. Ann Mortimer             |
+--------+--------+-----------------+--------------------------------+
| 305    | UK     | 2/4             | Anthony Maden, M.D.            |
+--------+--------+-----------------+--------------------------------+
| 401    | France | 17/16           | Prof. Marc Bourgeois           |
+--------+--------+-----------------+--------------------------------+
| 402    | France | 5/6             | Marie-Agathe Zimmermann, M.D.  |
+--------+--------+-----------------+--------------------------------+
| 403    | France | 11/11           | Frederic Khidichian, M.D.      |
+--------+--------+-----------------+--------------------------------+
| 404    | France | 6/6             | Muriel Maurel, M.D.            |
+--------+--------+-----------------+--------------------------------+
| 405    | France | 4/5             | Pierre-Michel Llorca, M.D.     |
+--------+--------+-----------------+--------------------------------+
| 406    | France | 7/6             | Prof. Jean Dalery              |
+--------+--------+-----------------+--------------------------------+
| 501    | Italy  | 2/2             | Prof. Alberto Giannelli, M.D.  |
+--------+--------+-----------------+--------------------------------+
| 502    | Italy  | 4/4             | Prof. Liliana Dell'Osso        |
+--------+--------+-----------------+--------------------------------+
| 505    | Italy  | 4/4             | Bernardo Carpiniello, M.D.     |
+--------+--------+-----------------+--------------------------------+
| 506    | Italy  | 3/2             | Rosaria Pioli, M.D.            |
+--------+--------+-----------------+--------------------------------+
| 601    | H      | 11/11           | Akos Kassai-Farkas, M.D.       |
|        | ungary |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 602    | H      | 16/16           | Eva Morik, M.D.                |
|        | ungary |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 604    | H      | 16/17           | Gyorgy Ostorharics-Horvath,    |
|        | ungary |                 | M.D.                           |
+--------+--------+-----------------+--------------------------------+
| 605    | H      | 6/6             | Laszlo Mod, M.D.               |
|        | ungary |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 701    | C      | 13/12           | Prof. Miro Jakovljevic         |
|        | roatia |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 702    | C      | 16/18           | Prof. Vera Folnegovic-Smale    |
|        | roatia |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 801    | S.     | 4/4             | Prof. Robin A. Emsley          |
|        | Africa |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 802    | S.     | 7/7             | Prof. Carllo Gagiano           |
|        | Africa |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 803    | S.     | 7/8             | Elisabeth Borkowska, M.D.      |
|        | Africa |                 |                                |
|        |        |                 | Mohamed Coovadia, M.D.         |
+--------+--------+-----------------+--------------------------------+
| 901    | Czech  | 5/6             | Jaroslav Hronek, M.D.          |
|        | Re     |                 |                                |
|        | public |                 | Vanda Benesova, M.D.           |
+--------+--------+-----------------+--------------------------------+
| 902    | Czech  | 7/7             | Zdenka Vyhnankova, M.D.        |
|        |        |                 |                                |
|        | Re     |                 |                                |
|        | public |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 903    | Czech  | 2/4             | Ivo Paclt, M.D.                |
|        |        |                 |                                |
|        | Re     |                 |                                |
|        | public |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 904    | Czech  | 5/5             | Libor Chvila, M.D.             |
|        | Re     |                 |                                |
|        | public |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 951    | Arg    | 5/4             | Pedro Rafael Gargoloff, M.D.   |
|        | entina |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 952    | Arg    | 7/6             | Liliana Avigo, M.D.            |
|        | entina |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 953    | Arg    | 5/6             | Luis Antonio Bengochea, M.D.   |
|        | entina |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 954    | Arg    | 5/5             | Carlos Alberto Morra, M.D.     |
|        | entina |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 955    | Arg    | 9/8             | Alberto Bertoldi, M.D.         |
|        | entina |                 |                                |
+--------+--------+-----------------+--------------------------------+
| 956    | Chile  | 17/16           | Veronica Larach, M.D.          |
+--------+--------+-----------------+--------------------------------+

+----------------------+------------------------+----------------------+
| **APPENDIX VI-2:**   |                        |                      |
|                      |                        |                      |
| **STUDY ABA 451**    |                        |                      |
|                      |                        |                      |
| **DISTRIBUTION OF    |                        |                      |
| CGI-SS-BP SCORES AT  |                        |                      |
| BASELINE**           |                        |                      |
+----------------------+------------------------+----------------------+
| **Baseline CGI-SS-BP | **Clozaril (N=490)**   | **Zyprexa (N=490)**  |
| Score**              |                        |                      |
|                      | **n (n/N%)**           | **n (n/N%)**         |
+----------------------+------------------------+----------------------+
| 1 (not at all        | 152 (31%)              | 153 (31%)            |
| suicidal)            |                        |                      |
+----------------------+------------------------+----------------------+
| 2 (mildly suicidal)  | 131 (27%)              | 132 (27%)            |
+----------------------+------------------------+----------------------+
| 3 (moderately        | 140 (29%)              | 141 (29%)            |
| suicidal)            |                        |                      |
+----------------------+------------------------+----------------------+
| 4 (severely          | 58 (12%)               | 51 (10%)             |
| suicidal)            |                        |                      |
+----------------------+------------------------+----------------------+
| 5 (attempted         | 3 (\<1%)               | 4 (\<1%)             |
| suicide)             |                        |                      |
+----------------------+------------------------+----------------------+
| Missing              | 6 (1%)                 | 9 (2%)               |
+----------------------+------------------------+----------------------+

+-------------------------------------+---------------+---------------+
| **appendix vi-3**                   |               |               |
|                                     |               |               |
| **study aba 451**                   |               |               |
|                                     |               |               |
| **enumeration of dropouts by        |               |               |
| reason**                            |               |               |
+-------------------------------------+---------------+---------------+
| **Reason for Discontinuation**      | **Clozaril**  | **Zyprexa**   |
|                                     |               |               |
|                                     | **N=490**     | **N=490**     |
+-------------------------------------+---------------+---------------+
| Adverse Events (incl. death)        | 49            | 38            |
+-------------------------------------+---------------+---------------+
| Abnormal Laboratory Value/Test      | 3             | 0             |
| Result                              |               |               |
+-------------------------------------+---------------+---------------+
| Unsatisfactory Effect on Psychosis  | 5             | 9             |
+-------------------------------------+---------------+---------------+
| Unsatisfactory Effect on Suicide    | 0             | 6             |
| Risk                                |               |               |
+-------------------------------------+---------------+---------------+
| Protocol Violation                  | 29            | 20            |
+-------------------------------------+---------------+---------------+
| Withdrawn Consent                   | 50            | 49            |
+-------------------------------------+---------------+---------------+
| Lost to Follow-Up                   | 33            | 39            |
+-------------------------------------+---------------+---------------+
| Administrative Reason               | 23            | 26            |
+-------------------------------------+---------------+---------------+
| **TOTAL DISCONTINUATIONS**          | **192**       | **187**       |
+-------------------------------------+---------------+---------------+

+-------------------------+---------------------+----------------------+
| **appendix vi-4**       |                     |                      |
|                         |                     |                      |
| **study aba 451**       |                     |                      |
|                         |                     |                      |
| **patients in-study by  |                     |                      |
| visit**                 |                     |                      |
+-------------------------+---------------------+----------------------+
| **Visit (week)**        | **Clozaril**        | **Zyprexa**          |
|                         |                     |                      |
|                         | **n (% of ITT)**    | **n (% of ITT)**     |
+-------------------------+---------------------+----------------------+
| 8                       | 411 (84%)           | 432 (88%)            |
+-------------------------+---------------------+----------------------+
| 16                      | 382 (78%)           | 414 (85%)            |
+-------------------------+---------------------+----------------------+
| 24                      | 361 (74%)           | 399 (81%)            |
+-------------------------+---------------------+----------------------+
| 32                      | 356 (73%)           | 382 (78%)            |
+-------------------------+---------------------+----------------------+
| 40                      | 344 (70%)           | 370 (76%)            |
+-------------------------+---------------------+----------------------+
| 48                      | 338 (69%)           | 364 (74%)            |
+-------------------------+---------------------+----------------------+
| 52                      | 337 (69%)           | 362 (74%)            |
+-------------------------+---------------------+----------------------+
| 60                      | 327 (67%)           | 352 (72%)            |
+-------------------------+---------------------+----------------------+
| 68                      | 318 (65%)           | 344 (70%)            |
+-------------------------+---------------------+----------------------+
| 80                      | 308 (63%)           | 324 (66%)            |
+-------------------------+---------------------+----------------------+
| 92                      | 304 (62%)           | 314 (64%)            |
+-------------------------+---------------------+----------------------+
| 104                     | 298 (61%)           | 303 (62%)            |
+-------------------------+---------------------+----------------------+

+------------------------+---------------------+----------------------+
| **appendix vi-5**      |                     |                      |
|                        |                     |                      |
| **study aba 451**      |                     |                      |
|                        |                     |                      |
| **median prescribed    |                     |                      |
| doses (mg/day) by      |                     |                      |
| visit**[^22]           |                     |                      |
+------------------------+---------------------+----------------------+
| **Visit (week)**       | **Clozaril**        | **Zyprexa**          |
+------------------------+---------------------+----------------------+
| 8                      | 250.0               | 15.0                 |
+------------------------+---------------------+----------------------+
| 16                     | 300.0               | 20.0                 |
+------------------------+---------------------+----------------------+
| 24                     | 300.0               | 20.0                 |
+------------------------+---------------------+----------------------+
| 32                     | 300.0               | 20.0                 |
+------------------------+---------------------+----------------------+
| 40                     | 300.0               | 20.0                 |
+------------------------+---------------------+----------------------+
| 48                     | 300.0               | 20.0                 |
+------------------------+---------------------+----------------------+
| 52                     | 300.0               | 20.0                 |
+------------------------+---------------------+----------------------+
| 60                     | 300.0               | 20.0                 |
+------------------------+---------------------+----------------------+
| 68                     | 300.0               | 20.0                 |
+------------------------+---------------------+----------------------+
| 80                     | 300.0               | 20.0                 |
+------------------------+---------------------+----------------------+
| 92                     | 300.0               | 20.0                 |
+------------------------+---------------------+----------------------+
| 104                    | 300.0               | 20.0                 |
+------------------------+---------------------+----------------------+

+-------------------+-----------+-----------+-----------+-----------+
| **appendix vi-6** |           |           |           |           |
|                   |           |           |           |           |
| **study aba 451** |           |           |           |           |
|                   |           |           |           |           |
| **enumeration of  |           |           |           |           |
| patients with     |           |           |           |           |
| concomitant       |           |           |           |           |
| psychotropic      |           |           |           |           |
| medication        |           |           |           |           |
| usage**[^23]      |           |           |           |           |
+-------------------+-----------+-----------+-----------+-----------+
| **Medication**    | **C       |           | **        |           |
|                   | lozaril** |           | Zyprexa** |           |
| **Class**         |           |           |           |           |
+-------------------+-----------+-----------+-----------+-----------+
|                   | **All     | **A       | **All     | **A       |
|                   | Usage**   | nalysis** | Usage**   | nalysis** |
|                   |           |           |           |           |
|                   |           | **Usage** |           | **Usage** |
+-------------------+-----------+-----------+-----------+-----------+
| Antipsychotics    | 429       | 410       | 413       | 390       |
+-------------------+-----------+-----------+-----------+-----------+
| Antidepressants   | 269       | 241       | 301       | 270       |
+-------------------+-----------+-----------+-----------+-----------+
| Sed/Anxiolytics   | 341       | 295       | 363       | 325       |
+-------------------+-----------+-----------+-----------+-----------+
| Mood Stabilizers  | 147       | 120       | 154       | 144       |
+-------------------+-----------+-----------+-----------+-----------+

+------------------------+--------------+--------------+--------------+
| **appendix vi-7**      |              |              |              |
|                        |              |              |              |
| **study aba 451**      |              |              |              |
|                        |              |              |              |
| **overall least        |              |              |              |
| squares mean dosage**  |              |              |              |
|                        |              |              |              |
| **by concomitant       |              |              |              |
| medication class and   |              |              |              |
| treatment group**      |              |              |              |
+------------------------+--------------+--------------+--------------+
| **Medication Class**   | **Clozaril** | **Zyprexa**  | **p-value**  |
+------------------------+--------------+--------------+--------------+
| Antipsychotics         | 2.1          | 3.8          | 0.0002       |
+------------------------+--------------+--------------+--------------+
| Antidepressants        | 16.7         | 20.7         | 0.0014       |
+------------------------+--------------+--------------+--------------+
| Sed/Anxiolytics        | 6.3          | 10.1         | \<0.0001     |
+------------------------+--------------+--------------+--------------+
| Mood Stabilizers       | 487          | 621          | 0.0107       |
+------------------------+--------------+--------------+--------------+

+------------------------+--------------+--------------+--------------+
| **appendix vi-8**      |              |              |              |
|                        |              |              |              |
| **study aba 451**      |              |              |              |
|                        |              |              |              |
| **least squares mean   |              |              |              |
| dosage for concomitant |              |              |              |
| antipsychotic usage by |              |              |              |
| treatment interval**   |              |              |              |
+------------------------+--------------+--------------+--------------+
| **Interval**           | **Clozaril** | **Zyprexa**  | **p-value**  |
+------------------------+--------------+--------------+--------------+
| 1-6 months             | 2.7          | 3.9          | 0.0060       |
+------------------------+--------------+--------------+--------------+
| 7-12 months            | 1.1          | 3.3          | \<0.0001     |
+------------------------+--------------+--------------+--------------+
| 13-18 months           | 1.1          | 3.5          | \<0.0001     |
+------------------------+--------------+--------------+--------------+
| 19-24 months           | 1.2          | 3.4          | \<0.0001     |
+------------------------+--------------+--------------+--------------+

+------------------------+--------------+--------------+--------------+
| **appendix vi-9**      |              |              |              |
|                        |              |              |              |
| **study aba 451**      |              |              |              |
|                        |              |              |              |
| **least squares mean   |              |              |              |
| dosage for concomitant |              |              |              |
| antidepressant usage   |              |              |              |
| by treatment           |              |              |              |
| interval**             |              |              |              |
+------------------------+--------------+--------------+--------------+
| **Interval**           | **Clozaril** | **Zyprexa**  | **p-value**  |
+------------------------+--------------+--------------+--------------+
| 1-6 months             | 15.9         | 19.4         | 0.0005       |
+------------------------+--------------+--------------+--------------+
| 7-12 months            | 15.4         | 20.4         | 0.0032       |
+------------------------+--------------+--------------+--------------+
| 13-18 months           | 16.9         | 19.7         | 0.1106       |
+------------------------+--------------+--------------+--------------+
| 19-24 months           | 18.1         | 21.2         | 0.0914       |
+------------------------+--------------+--------------+--------------+

+------------------------+--------------+--------------+--------------+
| **appendix vi-10**     |              |              |              |
|                        |              |              |              |
| **study aba 451**      |              |              |              |
|                        |              |              |              |
| **least squares mean   |              |              |              |
| dosage for concomitant |              |              |              |
| sedative/anxiolytic    |              |              |              |
| usage by treatment     |              |              |              |
| interval**             |              |              |              |
+------------------------+--------------+--------------+--------------+
| **Interval**           | **Clozaril** | **Zyprexa**  | **p-value**  |
+------------------------+--------------+--------------+--------------+
| 1-6 months             | 6.8          | 10.1         | 0.0001       |
+------------------------+--------------+--------------+--------------+
| 7-12 months            | 5.5          | 9.1          | 0.0002       |
+------------------------+--------------+--------------+--------------+
| 13-18 months           | 5.7          | 10.4         | 0.0002       |
+------------------------+--------------+--------------+--------------+
| 19-24 months           | 6.3          | 10.7         | 0.0027       |
+------------------------+--------------+--------------+--------------+

+------------------------+--------------+--------------+--------------+
| **appendix vi-11**     |              |              |              |
|                        |              |              |              |
| **study aba 451**      |              |              |              |
|                        |              |              |              |
| **least squares mean   |              |              |              |
| dosage for             |              |              |              |
| concomitant**          |              |              |              |
|                        |              |              |              |
| **mood stabilizer      |              |              |              |
| usage by treatment     |              |              |              |
| interval**             |              |              |              |
+------------------------+--------------+--------------+--------------+
| **Interval**           | **Clozaril** | **Zyprexa**  | **p-value**  |
+------------------------+--------------+--------------+--------------+
| 1-6 months             | 473.2        | 573.4        | 0.0166       |
+------------------------+--------------+--------------+--------------+
| 7-12 months            | 441.6        | 638.7        | 0.0022       |
+------------------------+--------------+--------------+--------------+
| 13-18 months           | 455.2        | 618.3        | 0.0253       |
+------------------------+--------------+--------------+--------------+
| 19-24 months           | 493.1        | 592.7        | 0.2157       |
+------------------------+--------------+--------------+--------------+

**APPENDIX VI-12**

**STUDY ABA 451**

**PRIMARY SUICIDALITY EFFICACY ANALYSIS:**

**MULTIPLE EVENTS ANALYSIS OF TIME TO FIRST**

**TYPE 1 OR TYPE 2 EVENT (ITT POPULATION)**

![](media/image3.png){width="5.997916666666667in" height="2.9375in"}

**APPENDIX VI-13**

**STUDY ABA 451**

**KAPLAN-MEIER SURVIVAL CURVES FOR TYPE 1 EVENTS**

![](media/image4.png){width="5.998611111111111in"
height="3.5722222222222224in"}

**APPENDIX VI-14**

**STUDY ABA 451**

**KAPLAN-MEIER SURVIVAL CURVES FOR TYPE 2 EVENTS**

![](media/image5.png){width="5.999305555555556in"
height="3.5840277777777776in"}

**APPENDIX VI-15**

**STUDY ABA 451**

**KAPLAN-MEIER ESTIMATES OF THE CUMULATIVE PROBABILITY OF A TYPE 1 OR
TYPE 2 EVENT BY VISIT**

![](media/image6.png){width="6.048611111111111in"
height="3.966666666666667in"}

**APPENDIX VI-16**

**STUDY ABA 451**

**COVARIATE ANALYSIS OF TIME TO TYPE 1 EVENT**

**USING A FULL COX PROPORTIONAL HAZARDS MODEL**

![](media/image7.png){width="5.25in" height="4.866666666666666in"}

**APPENDIX VI-17**

**STUDY ABA 451**

**MULTIPLE EVENT ANALYSIS OF TIME TO TYPE 1 AND TYPE 2 EVENTS**

**BY DIAGNOSTIC SUBGROUP**

![](media/image8.png){width="7.208333333333333in"
height="3.5833333333333335in"}

**APPENDIX VI-18**

**STUDY ABA 451**

**MULTIPLE EVENT ANALYSIS OF TIME TO TYPE 1 AND TYPE 2 EVENTS**

**BY GEOGRAPHIC SUBGROUP**

![](media/image9.png){width="6.791666666666667in" height="3.4in"}

+-----------------------------------------------------------------------+
| **appendix VI-19**                                                    |
|                                                                       |
| **case report forms audited for efficacy data**                       |
|                                                                       |
| **(by center-patient)**                                               |
+-----------------------------------------------------------------------+
| **Patients without a Type 1 or Type 2 Event**                         |
+-----------------------------------------------------------------------+
| 112-0020                                                              |
|                                                                       |
| 114-0033                                                              |
|                                                                       |
| 201-0011                                                              |
|                                                                       |
| 601-0020                                                              |
|                                                                       |
| 604-0021                                                              |
|                                                                       |
| 902-0004                                                              |
|                                                                       |
| 956-0032                                                              |
+-----------------------------------------------------------------------+
| **Patients with a Type 1 or Type 2 Event**                            |
+-----------------------------------------------------------------------+
| 102-0012                                                              |
|                                                                       |
| 105-0030                                                              |
|                                                                       |
| 112-0005                                                              |
|                                                                       |
| 116-0002                                                              |
|                                                                       |
| 120-0006                                                              |
|                                                                       |
| 122-0010                                                              |
|                                                                       |
| 127-0007                                                              |
|                                                                       |
| 201-0004                                                              |
|                                                                       |
| 304-0005                                                              |
|                                                                       |
| 401-0029                                                              |
|                                                                       |
| 406-0004                                                              |
|                                                                       |
| 604-0032                                                              |
|                                                                       |
| 702-0004                                                              |
|                                                                       |
| 954-0003                                                              |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **APPENDIX VI-20**                                                    |
|                                                                       |
| **Audit of Efficacy Data**                                            |
|                                                                       |
| **CRF Forms Examined**                                                |
+-----------------------------------------------------------------------+
| Adverse Events                                                        |
+-----------------------------------------------------------------------+
| Clinical Global Impression for Severity of Suicidality by Blinded     |
| Psychiatrist                                                          |
+-----------------------------------------------------------------------+
| Imminent Risk of Suicide Requiring Hospitalization                    |
+-----------------------------------------------------------------------+
| Suicide Attempt Form                                                  |
+-----------------------------------------------------------------------+
| Suicide Event Form-Blinded Psychiatrist                               |
+-----------------------------------------------------------------------+
| Suicide Event Form-Suicide Monitoring Board                           |
+-----------------------------------------------------------------------+

+-------+----+---+---+------+---------+--------------------------------+
| **app |    |   |   |      |         |                                |
| endix |    |   |   |      |         |                                |
| vii   |    |   |   |      |         |                                |
| -1:** |    |   |   |      |         |                                |
|       |    |   |   |      |         |                                |
| *     |    |   |   |      |         |                                |
| *line |    |   |   |      |         |                                |
| li    |    |   |   |      |         |                                |
| sting |    |   |   |      |         |                                |
| of    |    |   |   |      |         |                                |
| all   |    |   |   |      |         |                                |
| d     |    |   |   |      |         |                                |
| eaths |    |   |   |      |         |                                |
| (     |    |   |   |      |         |                                |
| Study |    |   |   |      |         |                                |
| ABA   |    |   |   |      |         |                                |
| 4     |    |   |   |      |         |                                |
| 51)** |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| *     | *  | * | * |      | **Days  | **Cause of Death**             |
| *Cent | *A | * | * |      | of TX** |                                |
| er/** | ge | S | L |      |         |                                |
|       | ** | e | a |      | *       |                                |
| **    |    | x | s |      | *\[post |                                |
| Subje |    | * | t |      | -TX\]** |                                |
| ct#** |    | * | D |      |         |                                |
|       |    |   | o |      |         |                                |
|       |    |   | s |      |         |                                |
|       |    |   | e |      |         |                                |
|       |    |   | * |      |         |                                |
|       |    |   | * |      |         |                                |
|       |    |   |   |      |         |                                |
|       |    |   | * |      |         |                                |
|       |    |   | * |      |         |                                |
|       |    |   | ( |      |         |                                |
|       |    |   | m |      |         |                                |
|       |    |   | g |      |         |                                |
|       |    |   | / |      |         |                                |
|       |    |   | d |      |         |                                |
|       |    |   | a |      |         |                                |
|       |    |   | y |      |         |                                |
|       |    |   | ) |      |         |                                |
|       |    |   | * |      |         |                                |
|       |    |   | * |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| **CLO |    |   |   |      |         |                                |
| ZARIL |    |   |   |      |         |                                |
| PATIE |    |   |   |      |         |                                |
| NTS** |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 101   | 56 | F |   | 300  | 106     | Unknown                        |
| /0016 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 114   | 31 | M |   | 400  | 278     | Pulmonary Embolism             |
| /0003 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 117   | 37 | M |   | 50   | 261     | Unknown                        |
| /0004 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 122   | 20 | M |   | 400  | 30      | Suicide                        |
| /0010 |    |   |   |      | \[+45\] |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 125   | 37 | F |   | 500  | 393     | Unknown                        |
| /0027 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 132   | 33 | F |   | 25   | 64      | Overdose (oxycodone)           |
| /0001 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 302   | 35 | M |   | 450  | 526     | Cardiac Arrest                 |
| /0010 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 303   | 35 | F |   | 100  | 70      | Complications 2° Suicide       |
| /0010 |    |   |   |      | 3\[+?\] | Attempt                        |
+-------+----+---+---+------+---------+--------------------------------+
| 401   | 36 | M |   | 200  | 26      | Suicide                        |
| /0001 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 401   | 46 | F |   | 325  | 15      | Cancer                         |
| /0022 |    |   |   |      | \[+19\] |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 702   | 38 | M |   | 250  | 7       | Suicide                        |
| /0010 |    |   |   |      | 9\[+1\] |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 802   | 37 | M |   | 200  | 225\    | Motor Vehicle Accident         |
| /0012 |    |   |   |      | [+139\] |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 902   | 42 | M |   | 150  | 417     | Suicide                        |
| /0002 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| **ZY  |    |   |   |      |         |                                |
| PREXA |    |   |   |      |         |                                |
| PATIE |    |   |   |      |         |                                |
| NTS** |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 105   | 40 | F |   | 20   | 770     | Overdose (narcotics)           |
| /0007 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 112   | 47 | M |   | 15   | 15      | Overdose (heroin)              |
| /0019 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 117   | 32 | M |   | 20   | 82      | Unknown                        |
| /0005 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 301   | 40 | M |   | 15   | 82      | Suicide                        |
| /0002 |    |   |   |      | \[+15\] |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 302   | 48 | F |   | 0    | 0       | Myocardial Infarction (prior   |
| /0007 |    |   |   |      |         | to TX)                         |
+-------+----+---+---+------+---------+--------------------------------+
| 302   | 58 | M |   | 20   | 48      | Cancer                         |
| /0012 |    |   |   |      | 2\[+6\] |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 303   | 21 | M |   | 10   | 19\     | Suicide                        |
| /0022 |    |   |   |      | [+132\] |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 953   | 60 | F |   | 10   | 695     | Unknown                        |
| /0007 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+
| 953   | 54 | F |   | 20   | 66      | Stroke                         |
| /0011 |    |   |   |      |         |                                |
+-------+----+---+---+------+---------+--------------------------------+

+--------------------------------------+--------------+---------------+
| **appendix VII-2**                   |              |               |
|                                      |              |               |
| **ENUMERATION OF serious adverse     |              |               |
| events AMONG CLOZARIL-TREATED        |              |               |
| PATIENTS**[^24]                      |              |               |
|                                      |              |               |
| **study aba 451**                    |              |               |
+======================================+==============+===============+
| **Body System/MedDRA Preferred       | **Number (%) |               |
| Term**                               | of Pts.      |               |
|                                      | Reporting    |               |
|                                      | SAE**        |               |
+--------------------------------------+--------------+---------------+
|                                      | **Clozaril** | **Zyprexa**   |
|                                      |              |               |
|                                      | **(N=479)**  | **(N=477)**   |
+--------------------------------------+--------------+---------------+
| **CARDIAC DISORDERS**                | 9 (1.9%)     | 7 (1.5%)      |
+--------------------------------------+--------------+---------------+
| Angina Pectoris                      | 2 (0.4%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Arrhythmia NOS                       | 3 (0.6%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Cardiomegaly NOS                     | 3 (0.6%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Coronary Artery Disease NOS          | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Myocardial Infarction                | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Pericarditis NOS                     | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **EAR AND LABYRINTH DISORDERS**      | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Vertigo NEC                          | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **ENDOCRINE DISORDERS**              | 2 (0.4%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Hypothyroidism                       | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Thyroid Disorder NOS                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **EYE DISORDERS**                    | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Conjunctivitis NEC                   | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **GASTROINTESTINAL DISORDERS**       | 19 (4.0%)    | 12 (2.5%)     |
+--------------------------------------+--------------+---------------+
| Abdominal Distention                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Abdominal Pain NOS                   | 5 (1.0%)     | 4 (0.8%)      |
+--------------------------------------+--------------+---------------+
| Abdominal Pain Upper                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Appendicitis Perforated              | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Colitis Ulcerative                   | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Constipation                         | 2 (0.4%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Gastric Ulcer Hemorrhage             | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Gastritis NOS                        | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Gastrointestinal Hemorrhage NOS      | 2 (0.4%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Hematemesis                          | 2 (0.4%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Hiatus Hernia                        | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Incisional Hernia NOS                | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Inguinal Hernia NOS                  | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Intestinal Obstruction NOS           | 3 (0.6%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Irritable Bowel Syndrome             | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Malabsorption                        | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Nausea                               | 2 (0.4%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Esophageal Stenosis                  | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Esophagitis NOS                      | 2 (0.4%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Pancreatitis NOS                     | 1 (0.2%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Proctitis NOS                        | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Reflux Esophagitis                   | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Vomiting NOS                         | 5 (1.0%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| **GENERAL DISORDERS/ADMINISTRATION   | 10 (2.1%)    | 7 (1.5%)      |
| SITE CONDITIONS**                    |              |               |
+--------------------------------------+--------------+---------------+
| Chest Pain NEC                       | 5 (1.0%)     | 5 (1.0%)      |
+--------------------------------------+--------------+---------------+
| Fall                                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Fatigue                              | 2 (0.4%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Neuroleptic Malignant Syndrome       | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Pyrexia                              | 2 (0.4%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **HEPATOBILIARY DISORDERS**          | 4 (0.8%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Cholelithiasis                       | 3 (0.6%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Hepatic Disorder NOS                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **INFECTIONS AND INFESTATIONS**      | 18 (3.8%)    | 11 (2.3%)     |
+--------------------------------------+--------------+---------------+
| Abscess NOS                          | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Bronchopneumonia NOS                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Cellulitis Gangrenous                | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Colitis Pseudomembranous             | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Hepatitis Viral NOS                  | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Lung Infection NOS                   | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Meningitis Pneumococcal              | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Peritoneal Abscess                   | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Pneumonia NOS                        | 7 (1.5%)     | 4 (0.8%)      |
+--------------------------------------+--------------+---------------+
| Pyelonephritis NOS                   | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Salpingitis NOS                      | 1 (0.5%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Sepsis NOS                           | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Skin Infection NOS                   | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Upper Respiratory Tract Infection    | 1 (0.2%)     | 0 (0.0%)      |
| NOS                                  |              |               |
+--------------------------------------+--------------+---------------+
| Viral Infection NOS                  | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Vulvovaginitis Trichomonal           | 1 (0.5%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **INJURY AND POISONING**             | 18 (3.8%)    | 17 (3.6%)     |
+--------------------------------------+--------------+---------------+
| Accident NOS                         | 2 (0.4%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Accidental Overdose (therapeutic     | 4 (0.8%)     | 2 (0.4%)      |
| agent)                               |              |               |
+--------------------------------------+--------------+---------------+
| Alcohol Intoxication Acute           | 1 (0.2%)     | 4 (0.8%)      |
+--------------------------------------+--------------+---------------+
| Ankle Fracture                       | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Burns NOS                            | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Drug Toxicity NOS                    | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Forearm Fracture                     | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Non-accidental Overdose              | 5 (1.0%)     | 4 (0.8%)      |
+--------------------------------------+--------------+---------------+
| Overdose NOS                         | 2 (0.4%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Self Mutilation                      | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Wrist Fracture                       | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **INVESTIGATIONS**                   | 11 (2.3%)    | 3 (0.6%)      |
+--------------------------------------+--------------+---------------+
| Blood Test NOS                       | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Hemoglobin Decreased                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Platelet Count Decreased             | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| White Blood Cell Decreased           | 8 (1.7%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **METABOLISM AND NUTRITION           | 13 (2.7%)    | 7 (1.5%)      |
| DISORDERS**                          |              |               |
+--------------------------------------+--------------+---------------+
| Dehydration                          | 4 (0.8%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Diabetes Mellitus NOS                | 4 (0.8%)     | 6 (1.3%)      |
+--------------------------------------+--------------+---------------+
| Hyperglycemia                        | 3 (0.6%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Hypokalemia                          | 2 (0.4%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Ketoacidosis                         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Polydipsia                           | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Tetany                               | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **MUSCULOSKELETAL/CONNECTIVE         | 5 (1.0%)     | 3 (0.6%)      |
| TISSUE/BONE DISORDERS**              |              |               |
+--------------------------------------+--------------+---------------+
| Back Pain                            | 2 (0.4%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Muscle Twitching                     | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Pain in Limb                         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Pseudoarthrosis                      | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Rhabdomyolysis                       | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Sensation of Heaviness               | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **NEOPLASMS BENIGN AND MALIGNANT**   | 4 (0.8%)     | 4 (0.8%)      |
+--------------------------------------+--------------+---------------+
| Basal Cell Carcinoma                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Breast Lump NOS                      | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Lymphoma NOS                         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Uterine Cancer NOS                   | 1 (0.5%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **NERVOUS SYSTEM DISORDERS**         | 26 (5.4%)    | 15 (3.1%)     |
+--------------------------------------+--------------+---------------+
| Cerebrovascular Accident NOS         | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Complex Partial Seizures             | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Convulsions NOS                      | 4 (0.8%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Disturbance in Attention NEC         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Dizziness (excl. vertigo)            | 3 (0.6%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Dyskinesia NEC                       | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Dysphonia                            | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Epilepsy NOS                         | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Grand Mal Convulsion                 | 1 (0.2%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Hypotonia                            | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Insomnia NEC                         | 3 (0.6%)     | 4 (0.8%)      |
+--------------------------------------+--------------+---------------+
| Myoclonic Seizure                    | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Paresthesia NEC                      | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Paraplegia                           | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Sedation                             | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Sleep Apnea Syndrome                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Somnolence                           | 3 (0.6%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Syncope                              | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Tremor NEC                           | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **PREGNANCY, PUERPERIUM, AND         | 2 (0.4%)     | 0 (0.0%)      |
| PERINATAL CONDITIONS**               |              |               |
+--------------------------------------+--------------+---------------+
| Intrauterine Death                   | 1 (0.5%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Placenta Previa                      | 1 (0.5%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Pregnancy NOS                        | 1 (0.5%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **PSYCHIATRIC DISORDERS**            | 185 (38.6%)  | 206 (43.2%)   |
+--------------------------------------+--------------+---------------+
| Abnormal Behavior NOS                | 2 (0.4%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Acute Psychosis                      | 3 (0.6%)     | 6 (1.3%)      |
+--------------------------------------+--------------+---------------+
| Aggression                           | 5 (1.0%)     | 7 (1.5%)      |
+--------------------------------------+--------------+---------------+
| Agitation                            | 9 (1.9%)     | 13 (2.7%)     |
+--------------------------------------+--------------+---------------+
| Agitation Aggravated                 | 3 (0.6%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Alcoholic Withdrawal Symptoms        | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Alcoholism                           | 5 (1.0%)     | 6 (1.3%)      |
+--------------------------------------+--------------+---------------+
| Anhedonia                            | 2 (0.4%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Anxiety NEC                          | 30 (6.3%)    | 38 (8.0%)     |
+--------------------------------------+--------------+---------------+
| Catatonia                            | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Completed Suicide                    | 5 (1.0%)     | 3 (0.6%)      |
+--------------------------------------+--------------+---------------+
| Confusion                            | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Confusional State                    | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Delirium                             | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Delusion NOS                         | 14 (2.9%)    | 16 (3.4%)     |
+--------------------------------------+--------------+---------------+
| Delusion of Grandeur                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Depressed Mood                       | 5 (1.0%)     | 8 (1.7%)      |
+--------------------------------------+--------------+---------------+
| Depression NEC                       | 42 (8.8%)    | 44 (9.2%)     |
+--------------------------------------+--------------+---------------+
| Drug Addiction                       | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Exacerbation of Anxiety              | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Hallucination NOS                    | 8 (1.7%)     | 11 (2.3%)     |
+--------------------------------------+--------------+---------------+
| Hallucination, Auditory              | 13 (2.7%)    | 25 (5.2%)     |
+--------------------------------------+--------------+---------------+
| Homicidal Ideation                   | 9 (1.9%)     | 7 (1.5%)      |
+--------------------------------------+--------------+---------------+
| Intentional Self-Injury              | 2 (0.4%)     | 4 (0.8%)      |
+--------------------------------------+--------------+---------------+
| Irritability                         | 1 (0.2%)     | 4 (0.8%)      |
+--------------------------------------+--------------+---------------+
| Major Depressive Disorder NOS        | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Mental Disorder NEC                  | 3 (0.6%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Obsessive Thoughts                   | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Obsessive-Compulsive Disorder        | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Panic Attack                         | 3 (0.6%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Paranoia                             | 7 (1.5%)     | 6 (1.3%)      |
+--------------------------------------+--------------+---------------+
| Psychomotor Retardation              | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Psychotic Disorder NOS               | 72 (15.0%)   | 75 (15.7%)    |
+--------------------------------------+--------------+---------------+
| Schizoaffective Disorder             | 6 (1.3%)     | 7 (1.5%)      |
+--------------------------------------+--------------+---------------+
| Schizophrenia NOS                    | 11 (2.3%)    | 15 (3.1%)     |
+--------------------------------------+--------------+---------------+
| Schizophrenia, Disorganized Type     | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Schizophrenia, Paranoid Type         | 2 (0.4%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Self-Induced Vomiting                | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Self-Injurious Ideation              | 2 (0.4%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Sleep Disorder NOS                   | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Stress Symptoms                      | 1 (0.2%)     | 3 (0.6%)      |
+--------------------------------------+--------------+---------------+
| Suicidal Ideation                    | 77 (16.1%)   | 109 (22.9%)   |
+--------------------------------------+--------------+---------------+
| Suicide Attempt                      | 32 (6.7%)    | 56 (11.7%)    |
+--------------------------------------+--------------+---------------+
| Tension                              | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Thinking Abnormal NEC                | 3 (0.6%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| **RENAL AND URINARY DISORDERS**      | 5 (1.0%)     | 3 (0.6%)      |
+--------------------------------------+--------------+---------------+
| Calculus Bladder                     | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Polyuria                             | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Renal Failure NOS                    | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Urinary Incontinence                 | 2 (0.4%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **REPRODUCTIVE SYSTEM AND BREAST     | 5 (1.0%)     | 2 (0.4%)      |
| DISORDERS**                          |              |               |
+--------------------------------------+--------------+---------------+
| Amenorrhea NOS                       | 1 (0.5%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Orchitis NOS                         | 1 (0.3%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Ovarian Cyst                         | 1 (0.5%)     | 1 (0.5%)      |
+--------------------------------------+--------------+---------------+
| Pelvic Pain NOS                      | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Vulval Ulceration                    | 1 (0.5%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **RESPIRATORY, THORACIC, AND         | 12 (2.5%)    | 7 (1.5%)      |
| MEDIASTINAL DISORDERS**              |              |               |
+--------------------------------------+--------------+---------------+
| Asthma NOS                           | 1 (0.2%)     | 3 (0.6%)      |
+--------------------------------------+--------------+---------------+
| Chronic Obstructive Airways Disease  | 1 (0.2%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Dyspnea                              | 3 (0.6%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Hyperventilation                     | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Hypoventilation                      | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Pharyngeal Disorder NOS              | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Pleural Effusion                     | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Pneumonia Aspiration                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Respiratory Distress                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Respiratory Failure (excl. neonatal) | 2 (0.4%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| **SKIN AND CUTANEOUS TISSUE          | 5 (1.0%)     | 1 (0.2%)      |
| DISORDERS**                          |              |               |
+--------------------------------------+--------------+---------------+
| Dermatitis Medicamentosa             | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Epidermal Cyst                       | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Hemangioma NOS                       | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Hidradenitis                         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Rash Papular                         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **SOCIAL CIRCUMSTANCES**             | 12 (2.5%)    | 18 (3.8%)     |
+--------------------------------------+--------------+---------------+
| Bereavement NOS                      | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Drug Abuse                           | 1 (0.2%)     | 5 (1.0%)      |
+--------------------------------------+--------------+---------------+
| Social Problem NOS                   | 11 (2.3%)    | 13 (2.7%)     |
+--------------------------------------+--------------+---------------+
| Treatment Noncompliance              | 1 (0.2%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| **SURGICAL AND MEDICAL PROCEDURES**  | 2 (0.4%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Hospitalization NOS                  | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Orthopedic Procedure                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **VASCULAR DISORDERS**               | 5 (1.0%)     | 5 (1.0%)      |
+--------------------------------------+--------------+---------------+
| Acute Circulatory Failure            | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Deep Venous Thrombosis NOS           | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Postural Hypotension                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Pulmonary Embolism                   | 2 (0.4%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Transient Ischemic Attack            | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+

+-----------------------+-----------------------+-----------------------+
| **appendix vii-3:**   |                       |                       |
|                       |                       |                       |
| **narrative summaries |                       |                       |
| reveiewed for         |                       |                       |
| patients with serious |                       |                       |
| adverse events**      |                       |                       |
|                       |                       |                       |
| **(by                 |                       |                       |
| center#-patient#)**   |                       |                       |
+-----------------------+-----------------------+-----------------------+
| 109-0016              | 126-0022              | 302-0041              |
|                       |                       |                       |
| 117-0004              | 129-0010              | 403-0008              |
|                       |                       |                       |
| 120-0003              | 301-0019              | 502-0008              |
|                       |                       |                       |
| 120-0014              | 302-0010              | 701-0022              |
|                       |                       |                       |
| 126-0017              | 302-0011              | 702-0021              |
+-----------------------+-----------------------+-----------------------+

+--------------------------------------+--------------+---------------+
| **appendix VII-4**                   |              |               |
|                                      |              |               |
| **ENUMERATION OF adverse events      |              |               |
| leading to dropout AMONG             |              |               |
| CLOZARIL-TREATED PATIENTS**[^25]     |              |               |
|                                      |              |               |
| **study aba 451**                    |              |               |
+======================================+==============+===============+
| **Body System/MedDRA Preferred       | **Number (%) |               |
| Term**                               | of Pts.      |               |
|                                      | with**       |               |
|                                      |              |               |
|                                      | **AE Leading |               |
|                                      | to Dropout** |               |
+--------------------------------------+--------------+---------------+
|                                      | **Clozaril** | **Zyprexa**   |
|                                      |              |               |
|                                      | **(N=479)**  | **(N=477)**   |
+--------------------------------------+--------------+---------------+
| **CARDIAC DISORDERS**                | 3 (0.6%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Cardiomegaly NOS                     | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Palpitations                         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Tachycardia NOS                      | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **EYE DISORDERS**                    | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Bloodshot Eye                        | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **GASTROINTESTINAL DISORDERS**       | 6 (1.3%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Abdominal Pain NOS                   | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Aptyalism                            | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Diarrhea NOS                         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Intestinal Obstruction NOS           | 3 (0.6%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Nausea                               | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Salivary Hypersecretion              | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Vomiting NOS                         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **GENERAL DISORDERS/ADMINISTRATION   | 1 (0.2%)     | 0 (0.0%)      |
| SITE CONDITIONS**                    |              |               |
+--------------------------------------+--------------+---------------+
| Pyrexia                              | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **INVESTIGATIONS**                   | 11 (2.3%)    | 8 (1.7%)      |
+--------------------------------------+--------------+---------------+
| Blood Test NOS                       | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Weight Increased                     | 2 (0.4%)     | 7 (1.5%)      |
+--------------------------------------+--------------+---------------+
| White Blood Cell Decreased           | 8 (1.7%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **METABOLISM AND NUTRITION           | 2 (0.4%)     | 2 (0.4%)      |
| DISORDERS**                          |              |               |
+--------------------------------------+--------------+---------------+
| Diabetes Mellitus NOS                | 1 (0.2%)     | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Hyperglycemia NOS                    | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **MUSCULOSKELETAL/CONNECTIVE         | 2 (0.4%)     | 1 (0.2%)      |
| TISSUE/BONE DISORDERS**              |              |               |
+--------------------------------------+--------------+---------------+
| Muscle Twitching                     | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Myalgia                              | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Sensation of Heaviness               | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **NEOPLASMS BENIGN AND MALIGNANT**   | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Lymphoma NOS                         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **NERVOUS SYSTEM DISORDERS**         | 11 (2.3%)    | 2 (0.4%)      |
+--------------------------------------+--------------+---------------+
| Cerebrovascular Accident NOS         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Disturbance in Attention NEC         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Dizziness (excl. vertigo)            | 4 (0.8%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Dysarthria                           | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Memory Impairment                    | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Sedation                             | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Somnolence                           | 5 (1.0%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Vegetative State Chronic             | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **PREGNANCY, PUERPERIUM, AND         | 1 (0.5%)     | 0 (0.0%)      |
| PERINATAL CONDITIONS**               |              |               |
+--------------------------------------+--------------+---------------+
| Pregnancy NOS                        | 1 (0.5%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| **PSYCHIATRIC DISORDERS**            | 12 (2.5%)    | 17 (3.6%)     |
+--------------------------------------+--------------+---------------+
| Acute Psychosis                      | 2 (0.4%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Agitation                            | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Anxiety NEC                          | 2 (0.4%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Depression NEC                       | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Irritability                         | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Obsessive-Compulsive Disorder        | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Paranoia                             | 2 (0.4%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+
| Psychotic Disorder NOS               | 2 (0.4%)     | 9 (1.9%)      |
+--------------------------------------+--------------+---------------+
| Suicidal Ideation                    | 1 (0.2%)     | 4 (0.8%)      |
+--------------------------------------+--------------+---------------+
| Suicide Attempt                      | 1 (0.2%)     | 3 (0.6%)      |
+--------------------------------------+--------------+---------------+
| **RENAL AND URINARY DISORDERS**      | 1 (0.2%)     | 1 (0.2%)      |
+--------------------------------------+--------------+---------------+
| Urinary Incontinence                 | 1 (0.2%)     | 0 (0.0%)      |
+--------------------------------------+--------------+---------------+

[^1]: American Psychiatric Association: *Diagnostic and Statistical
    Manual of Mental Disorders*, Fourth Edition. Washington, DC,
    American Psychiatric Association, 1994.

[^2]: See a clinical review by Dr. James Knudsen dated 2-10-93.

[^3]: Please see my Review and Evaluation of Clinical Data dated
    10-27-95 for a complete description of the ERI study design and
    findings.

[^4]: Meltzer HY and Okayli G. Reduction of Suicidality During Clozapine
    Treatment of Neuroleptic-Resistant Schizophrenia: Impact on
    Risk-Benefit Assessment. Am J Psychiatry 1995;152:183-190.

[^5]: See a Memorandum by Dr. Thomas Laughren dated 11-3-95.

[^6]: These figures are based on corrected data submitted to the Agency
    on 5-17-02.

[^7]: These assessments were conducted at baseline and at the following
    weeks: 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 60, 68,
    80, 92, and 104.

[^8]: Blinded assessments were done at baseline and at the following
    weeks: 8, 16, 24, 32, 40, 48, 52, 60, 68, 80, 92, and 104.

[^9]: Amendment #1 to the protocol added an increased level of
    surveillance for suicide risk as a primary outcome.

[^10]: Amendment #6 did not specify that time to either type of event or
    censoring would include time subsequent to premature termination for
    dropouts.

[^11]: Please see the statistical review for further discussion of the
    WLW methodology.

[^12]: Countries with small numbers of patients were pooled with other
    countries to form a "pooled country" factor that was used as a
    stratum in the statistical analyses. Pooled countries were grouped
    as follows: U.S. and Canada, S. Africa and the U.K., France and
    Italy, Argentina and Chile, Croatia and the Czech Republic, and
    Hungary.

[^13]: This information was submitted to the NDA on 6-24-02.

[^14]: Based on Fisher's exact test.

[^15]: A coefficient \<0 indicates that Clozaril was superior to
    Zyprexa.

[^16]: A hazard ratio \<1 indicates superiority of Clozaril over
    Zyprexa.

[^17]: The 95% CI's for the treatment group differences contained zero
    (implying no difference) up to and including the week 80 visit.

[^18]: Log rank test.

[^19]: See Appendix 5.3.1, Table 9.1-5, of the study report.

[^20]: N= total number of patients in subgroup, n= number of patients
    with event in subgroup, %= (n/N)×100%, KM %= Kaplan-Meier estimate
    of the cumulative probability of the event at week 104.

[^21]: ^?^ For example, see Newcomer JW, et al. Abnormalities in Glucose
    Regulation During Antipsychotic Treatment of Schizophrenia. Arch Gen
    Psychiatry. 2002;59:337-345.

[^22]: This information was provided by the sponsor in a 3-29-02
    submission.

[^23]: All Usage enumerates all patients who took at least one dose of
    concomitant medication in that class. Analysis Usage enumerates
    patients who took concomitant medication after analysis exclusion
    criteria were applied.

[^24]: Excludes SAE's reported only in Zyprexa patients. Denominators
    adjusted for gender, as appropriate.

[^25]: Excludes AE's leading to dropout only in Zyprexa patients.
    Denominators adjusted for gender.