# FDA Briefing Package

###### Anti-Infective Drugs Advisory Committee

**68^th^ Meeting**

###### March 24, 2000

**New Drug Applications 21-130, 21-131, 21-132**

**Zyvox™ (linezolid)**

# Table of Contents

# Summary of Selected Preclinical Information . . . . . . . . . . . . . . . . . . . . 1

####### Clinical Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

######## Clinical/Statistical Analyses of Phase III Trials . . . . . . . . . . . . . . . . . 5

####### Summary of Key Differences in Analytic Methodology . . . . . . . . . . . . . 6

**between FDA and Sponsor**

####### Community-Acquired Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

####### Nosocomial Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

**Uncomplicated Skin/Skin Structure Infections . . . . . . . . . . . . .
. . . . . 10**

**Complicated Skin/Skin/Structure Infections . . . . . . . . . . . . . .
. . . . . . . 11**

**Methicillin-resistant Staphylococcal Infections . . . . . . . . . . .
. . . . . . . . 12**

####### Vancomycin-Resistant Enterococcal Infections . . . . . . . . . . . . . . . . . . .13

######## Appendix -- Clinical Trial Review Methods . . . . . . . . . . . . . . . . . . . . . . 15

####### Efficacy Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

####### Safety Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

# Summary of Selected Preclinical Information 

# Chemistry

-   Totally synthetic

-   Belongs to oxazolidinone class of antimicrobials

# Mechanism of Action

-   Inhibits protein synthesis by action at novel site on 23S ribosomal
    RNA

# Pharmacokinetics/Pharmacodynamics

-   Parenteral and oral administration achieve nearly equivalent serum
    concentrations

-   Two major metabolites have no antibacterial activity

-   Key pharmacodynamic parameter - amount of time serum concentration
    exceeds the MIC

-   Mouse thigh model with *S. pneumoniae* showed efficacy achieved when
    concentration maintained above MIC for 40% of dosing interval

-   Approximately 31% protein bound

-   600 mg bid dose - maximum peak plasma concentration \[\~15 g/mL
    (IV); 21 g/mL (oral)\] occurs within 1 to 2 hours

-   600 mg bid dose - C~min~ \~3.68 g/mL (iv); \~6.15 g/mL (oral)

-   C~min~ near or above the highest MIC~90~ (4 g/mL) for target
    pathogens

[**Spectrum of Activity**]{.underline}

-   Primarily Gram-positive activity, including vancomycin, methicillin,
    and pencillin- resistant microorganisms

-   Bacteriostatic against staphylococci and enterococci

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-   Bactericidal against most strains of streptococci

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-   MIC~90~ (g/mL) range for target pathogens

*Staphylococcus* sp. (including methicillin-resistant and VISA strains):
1 -- 4

*Streptococcus pneumoniae* (including penicillin-resistant strains): 1
-- 2

*Streptococcus* sp. (other than *S. pneumoniae*): 1 -- 2

*Enterococcus* *faecium* and *faecalis* (including vancomycin-resistant
strains): 1 -- 4

-   Minimal activity against Gram-negative organisms

[MIC~90~ (g/mL)]{.underline}

*Haemophilus influenzae* -- 16

*Moraxella catarrhalis* -- 8

# Resistance

-   Has been induced in laboratory

-   Point mutation on 23S rRNA creating guanine to uracil transversion

-   Frequency \< 1 in 10^9^

-   Cross-resistance perhaps to lincosamides and chloramphenicol

-   Resistant organisms have occurred in patients (only *Enterococcus*
    sp. involved)

Fifteen cases as of 12/31/99

-   14 *Enterococcus faecium*

-   1 *Enterococcus faecalis*

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-   Resistance development in compassionate use trial (study 25)

> \- 705 patients enrolled; 501 with +Cx for enterococcus

-   9 cases of resistance developed (1.8%)

-   8 *E. faecium*, 1 *E. faecalis*

-   6 of 9 patients considered failures

-   3 of 9 patients considered cured

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-   Resistance development in VRE trial (studies 54A/54)

> \- 331 patients enrolled; treatment blind not broken for 104 patients
>
> \- 6 cases of resistance developed -- all *E. faecium*
>
> \- 2 cases in 600 mg (high dose) arm
>
> \- 1 patient considered cured
>
> \- 4 cases in 200 mg (low dose) arm
>
> \- 1 patient considered cured

# Other microbiologic characteristics of linezolid

-   Synergism with other antimicrobials not demonstrated

-   Antagonism -- chloramphenicol and lincosamides and perhaps
    quinolones

-   Post-antibiotic effect has been demonstrated but does not play a
    role in determining dosing regimen

-   Intracellular concentration -- penetrates neutrophils, and
    peripheral monocytes but does not accumulate in them

# II. Clinical Pharmacology

The sponsor has provided information about the pharmacokinetics of
linezolid in their package. However, several issues should be
considered:

1.  The pharmacokinetics of linezolid in humans are highly variable.
    After administration of multiple oral doses of 400 mg (twice daily),
    maximum plasma linezolid concentrations (C~max~) ranged from 5.9 to
    24 g/mL and minimum plasma concentrations (C~min~) ranged from 0.5
    to 7.1 g/mL. The area under the curve (AUC) ranged from 34 to 152 g
    h/mL. After administration of multiple oral doses of 600 mg (twice
    daily) the maximum plasma linezolid concentration (C~max~) ranged
    from 10 to 32 g/mL and minimum plasma concentrations (C~min~) ranged
    from 2 to 12.3 g/mL. The area under the curve (AUC) ranged from 68
    to 209 g h/mL.

> To determine if differences in body weight could explain this
> variability, the AUC values were normalized by dose/body weight
> (mg/kg). After normalization, AUC ranged from 6.93 to 33.9 µg·h/mL per
> mg/kg dose after 400 mg multiple oral dosing. AUC ranged from 11.2 to
> 23.8 µg·h /mL per mg/kg dose after 600 mg multiple oral dosing. Thus,
> differences in body weight explain some but not all of this
> variability. The results are listed in Table II.1.

+------------------------------+------------------+-------------------+
| **Table II.1.** Linezolid    |                  |                   |
| AUCs normalized for body     |                  |                   |
| weight                       |                  |                   |
+------------------------------+------------------+-------------------+
| Parameter                    | After 400 mg     | After 600 mg      |
|                              | multiple doses   | multiple doses    |
+------------------------------+------------------+-------------------+
| C~min~ (g/mL) (range, n=16)  | 0.5-7.1          | 10-32             |
+------------------------------+------------------+-------------------+
| C~max~ (g/mL) (range, n=16)  | 5.9 -24          | 2-12.3            |
+------------------------------+------------------+-------------------+
| AUC (g h/mL) (range, n=16)   | 34-152           | 68-209            |
+------------------------------+------------------+-------------------+
| AUC (g h/mL) per mg/kg dose  | 6.93-33.9        | 11.2-23.8         |
|                              |                  |                   |
| (range, n=16)                |                  |                   |
+------------------------------+------------------+-------------------+

2.  Linezolid is a reversible MAO-A and B inhibitor. Its inhibitory
    activity was compared in *in vitro* studies with known MAO
    inhibitors. The results are shown in Table II.2.

+--------+--------------------+----------+-----------+----------------+
| *      |                    |          |           |                |
| *Table |                    |          |           |                |
| II.2.  |                    |          |           |                |
| Comp   |                    |          |           |                |
| arison |                    |          |           |                |
| of MAO |                    |          |           |                |
| inhi   |                    |          |           |                |
| bitory |                    |          |           |                |
| ac     |                    |          |           |                |
| tivity |                    |          |           |                |
| of     |                    |          |           |                |
| lin    |                    |          |           |                |
| ezolid |                    |          |           |                |
| with   |                    |          |           |                |
| known  |                    |          |           |                |
| MAO    |                    |          |           |                |
| inhibi |                    |          |           |                |
| tors** |                    |          |           |                |
+--------+--------------------+----------+-----------+----------------+
| **     | **Inhibitor type** | **K~i~** |           | **Plasma       |
| Drug** |                    |          |           | c              |
|        |                    |          |           | oncentration** |
|        |                    |          |           |                |
|        |                    |          |           | **(C~max~)**   |
+--------+--------------------+----------+-----------+----------------+
|        |                    | MAO-A    | MAO-B     |                |
+--------+--------------------+----------+-----------+----------------+
| clor   | Irreversible MAO-A | 0.0013 M | 0.71 M    | N/A            |
| gyline | inhibitor          |          |           |                |
+--------+--------------------+----------+-----------+----------------+
| sele   | Irreversible MAO-B | 2 M      | 0.004 M   | 1 ng/mL        |
| giline | inhibitor          |          |           | (0.0045M)      |
|        |                    |          | (0.895    | after 10 mg    |
|        |                    |          | ng/mL)    | dose           |
+--------+--------------------+----------+-----------+----------------+
| lin    | Reversible MAO     | 56 M     | 0.71 M    | 18 g/mL (53.4  |
| ezolid | inhibitor          |          |           | M) after 600   |
|        |                    |          |           | mg dose        |
+--------+--------------------+----------+-----------+----------------+

> Comparison of K~i~ values shows linezolid to be a weak MAO inhibitor.
> However, the average maximal plasma concentration after a single 600
> mg dose of linezolid is about 18 g/mL (53.4 M) which is close to its
> K~i~ for MAO-A inhibition and much greater than its K~i~ for MAO-B
> inhibition, indicating that interaction with other sympathomimetic
> agents is likely. The sponsor conducted four *in vivo* studies to
> investigate the MAO inhibitory effect of linezolid; results from these
> studies may be found in the sponsor's briefing package. The four
> studies included a tyramine pressor test and drug-drug interaction
> studies with dextromethorphan, pseudoephedrine and
> phenylpropanolamine.
>
> In the tyramine pressor study, 100 mg of tyramine was required to
> raise systolic blood pressure by 30 mm Hg in healthy volunteers when
> linezolid was given at a dose of 625 mg twice daily.
>
> In the linezolid-dextromethorphan interaction study, patients received
> linezolid with dextromethorphan or with placebo. Temperature, blood
> pressure, and pulse were measured, a digit symbol substitution test
> (DSST) was administered, and the degree of sedation was determined.
> There were no statistically significant differences at any time point
> for DSST scores, temperature, systolic blood pressure, diastolic blood
> pressure, or pulse between dextromethorphan and linezolid plus
> dextromethorphan treatments. Sedation scores were assessed as "no
> sedation" for all subjects at all time points. No abnormal
> neurological findings were reported.
>
> In linezolid drug-drug interaction studies with pseudoephedrine or
> phenylpropanolamine, the maximum increases from baseline (at time 0)
> were measured for systolic blood pressure, diastolic blood pressure,
> and pulse, as well as the maximum systolic blood pressure, diastolic
> blood pressure and heart rate. Results were compared between patients
> receiving placebo alone, linezolid alone, pseudoephedrine alone,
> phenylpropanolamine alone, pseudoephedrine plus linezolid, or
> phenylpropanolamine plus linezolid. Based on the study results
> (detailed in the sponsor's package), the sponsor concluded that
> clinically significant interactions between linezolid and other drugs
> or tyramine-containing foods are unlikely. Although the results of
> drug-drug interaction studies were not significant, only one dose was
> studied for each drug (pseudoephedrine (60 mg), phenylpropanolamine
> (25 mg), dextromethorphan (20 mg)). Therefore, the relationship
> between dose and drug-drug interaction potential is not known.

3.  The pharmacokinetics of linezolid and its two major metabolites were
    studied in patients with renal impairment. Linezolid plasma
    concentrations were similar between healthy volunteers and renally
    impaired patients except that the AUC was 27% greater in anuric
    patients than in healthy volunteers. However, exposure to the two
    linezolid metabolites was significantly higher in renally impaired
    patients than in healthy volunteers. For metabolite 1 (PNU-142300),
    compared with the exposure (measured as AUC) in healthy volunteers,
    the total exposures were 53%, 631%, and 3516% greater in patients
    with moderate renal impairment, severe renal impairment, and anuria,
    respectively. Accordingly, the half-lives of metabolite 1 in these
    patients were increased. For metabolite 2 (PNU-142586), even more
    exposure was observed. Compared with the exposure (measured as AUC)
    in healthy volunteers, the total exposures to metabolite 2 were 68%,
    566% and 4744% greater in patients with moderate renal impairment,
    severe renal impairment, and anuria, respectively. The half-lives of
    this metabolite were also significantly increased. These increased
    half-lives will result in significant accumulation when repeated
    doses are given to patients with renal impairment. The clinical
    significance of such accumulation is unknown because the toxicity of
    these metabolites has not been studied in animals or humans.

# III. Clinical/Statistical Analyses of Phase III Trials of Linezolid

This section summarizes the FDA analyses of pivotal and supportive phase
III trials contained in New Drug Applications (NDAs) 21-130, 21-131, and
21-132 for Zyvox® (linezolid) injection, tablets, and suspension.
Pharmacia and Upjohn submitted these NDAs on October 15, 1999, to
support labeling of linezolid for the following indications in adults:

-   Nosocomial pneumonia, including cases with concurrent bacteremia,
    due to *Staphylococcus aureus* (methicillin-susceptible and
    resistant strains) or *Streptococcus pneumoniae*
    (penicillin-susceptible and resistant strains)

-   Community-acquired pneumonia, including cases with concurrent
    bacteremia, due to *Streptococcus pneumoniae*
    (penicillin-susceptible and resistant strains) or *Staphylococcus
    aureus* (methicillin-susceptible and resistant strains)

-   Uncomplicated skin and soft tissue infections due to *Staphylococcus
    aureus* (methicillin-susceptible and resistant strains),
    *Streptococcus pyogenes*, or *Streptococcus agalactiae*.

-   Complicated skin and soft tissues infections, including cases with
    concurrent bacteremia, due to *Staphylococcus aureus*
    (methicillin-susceptible and resistant strains), *Staphylococcus
    epidermidis* (methicillin-susceptible and resistant strains),
    *Streptococcus pyogenes*, or *Streptococcus agalactiae*.

-   Infections due to vancomycin-resistant *Enterococcus faecalis* and
    *Enterococcus faecium*, including cases with concurrent bacteremia.

The NDAs include data from pivotal controlled clinical trials of
linezolid for these indications as well as supportive data from
controlled trials of linezolid. The sponsor's development program has
also included studies of linezolid in the pediatric population. These
studies provide some clinical safety data on a total of 143 patients,
but the efficacy information from these open-label, non-comparative
studies should be interpreted with caution. Pharmacia & Upjohn has
proposed more pediatric studies, and has received a written request for
pediatric studies from the FDA. Details of the pediatric studies already
completed may be found in the sponsor's briefing package.

This briefing package concentrates on the FDA efficacy analyses of these
NDAs. Safety analyses are ongoing; methodology for the FDA safety
analysis may be found in the Appendix. Safety analyses to be presented
by the FDA at the Advisory Committee meeting will include discussion of
gastrointestinal and hematologic toxicities of linezolid, as well as
issues related to monoamine oxidase inhibition by linezolid.

# Summary Of Key Differences In Analytic Methodology Between FDA And Sponsor

A summary of methods used in the FDA analysis and a fuller description
of differences between the FDA's and sponsor's analytic methodology are
contained in the Appendix. Key areas of difference between the FDA's
analyses and the sponsor's include:

# Key differences in populations analyzed

-   For the pivotal VRE infection trial, which was designed to
    demonstrate superiority of linezolid 600 mg bid over linezolid 200
    mg bid, the FDA focused on a modified intent-to-treat (MITT)
    analysis that excluded patients without a documented VRE infection
    at baseline. The sponsor focused on the clinically evaluable (CE)
    and microbiologically evaluable (ME) populations.

-   For the other trials, the FDA examined ITT, MITT, CE, and ME
    populations. These were similar but not identical to the
    corresponding populations examined by the sponsor.

#### Key differences in assessment of clinical outcome

-   Deaths were generally classified as failures in the FDA ITT and MITT
    analyses.

-   In the sponsor's analyses, a fraction of deaths were considered
    indeterminate.

-   Generally, the sponsor considered patients with no post-baseline
    assessment as failures, whereas the FDA generally regarded live
    patients with no post-baseline assessments as missing.

> For full details on these differences, please refer to the Appendix.

**[Results]{.underline}**

[Community-Acquired Pneumonia]{.underline}

Pharmacia & Upjohn conducted two studies of community-acquired pneumonia
(Studies 33 and 51). Study 33 was a randomized, open-label trial in
patients requiring hospital admission for community-acquired pneumonia.
It compared IV linezolid 600 mg q12h followed by PO linezolid 600 mg
q12h with IV ceftriaxone 1 g q12h followed by PO cefpodoxime 200 mg
q12h. Details of the study design can be found in Pharmacia & Upjohn's
briefing package.

Table III.1 shows results of the FDA analysis of clinical outcome in
Study 33. The methods used by FDA reviewers to determine clinical
success rates are described in the Appendix. A total of 381 linezolid
subjects and 366 comparator subjects received at least one dose of study
drug. The numbers of subjects listed in Table III.1 exclude patients
with missing outcomes, except for analyses where missing outcomes were
changed to failures.

+------------------+---+----------+-----+-------------+--------------+
| **Table III.1.** |   |          |     |             |              |
| FDA Analysis of  |   |          |     |             |              |
| Clinical Outcome |   |          |     |             |              |
| in Study 33      |   |          |     |             |              |
| (open-label )    |   |          |     |             |              |
+------------------+---+----------+-----+-------------+--------------+
| **FDA-Defined**  | * |          | **C |             | **95%        |
|                  | * |          | eft |             | Confidence   |
| **Study          | L |          | ria |             | Interval**   |
| Population**     | i |          | xon |             |              |
|                  | n |          | e/c |             |              |
|                  | e |          | efp |             |              |
|                  | z |          | odo |             |              |
|                  | o |          | xim |             |              |
|                  | l |          | e** |             |              |
|                  | i |          |     |             |              |
|                  | d |          |     |             |              |
|                  | * |          |     |             |              |
|                  | * |          |     |             |              |
+------------------+---+----------+-----+-------------+--------------+
|                  | * | *        | **  | **Success   |              |
|                  | * | *Success | N** | Rates (%)** |              |
|                  | N | Rates    |     |             |              |
|                  | * | (%)**    |     |             |              |
|                  | * |          |     |             |              |
+------------------+---+----------+-----+-------------+--------------+
| ITT              | 3 | 80.9     | 313 | 77.0        | (-2.7, 10.5) |
|                  | 3 |          |     |             |              |
|                  | 0 |          |     |             |              |
+------------------+---+----------+-----+-------------+--------------+
| ITT (missing as  | 3 | 70.1     | 366 | 65.9        | (-2.7, 11.2) |
| failure)         | 8 |          |     |             |              |
|                  | 1 |          |     |             |              |
+------------------+---+----------+-----+-------------+--------------+
| MITT             | 1 | 83.5     | 117 | 76.9        | (-4.7, 17.8) |
|                  | 0 |          |     |             |              |
|                  | 9 |          |     |             |              |
+------------------+---+----------+-----+-------------+--------------+
| MITT (missing as | 1 | 71.1     | 126 | 71.4        | (-12.3,      |
| failure)         | 2 |          |     |             | 11.6)        |
|                  | 8 |          |     |             |              |
+------------------+---+----------+-----+-------------+--------------+
| FDA CE           | 2 | 86.3     | 274 | 82.1        | (-2.2, 10.6) |
|                  | 8 |          |     |             |              |
|                  | 5 |          |     |             |              |
+------------------+---+----------+-----+-------------+--------------+
| FDA ME           | 9 | 87.0     | 99  | 81.8        | (-6.2, 16.4) |
|                  | 2 |          |     |             |              |
+------------------+---+----------+-----+-------------+--------------+
| FDA bacteremic   | 3 | 90.3     | 26  | 61.5        | (3.8, 53.7)  |
| ME               | 1 |          |     |             |              |
+------------------+---+----------+-----+-------------+--------------+

Response rates in the FDA analyses were somewhat lower for both
treatment arms than in the sponsor's analyses. The 95% confidence
intervals around the difference in response rates between treatment arms
were similar in both the FDA analysis and the sponsor's analysis. The
confidence interval for the FDA analysis of bacteremic patients should
be interpreted with caution, since this represents a subset analysis
that was not prespecified.

Analyses that counted patients with missing outcomes as failures yielded
lower response rates, as expected. These analyses should be interpreted
with caution, since there were a significant number of patients with
missing outcomes, and many of these patients may not have been true
therapeutic failures.

Study 51 was a randomized, investigator-blind trial in subjects treated
as outpatients for community-acquired pneumonia. It compared PO
linezolid 600 mg q12h with PO cefpodoxime 200 mg q12h. Details of the
study design can be found in Pharmacia & Upjohn's briefing package.

Table III.2 shows results of the FDA analysis of clinical outcomes in
Study 51. The methods used by FDA reviewers to determine clinical
success rates are described in the Appendix. A total of 272 linezolid
subjects and 268 comparator subjects received at least one dose of study
drug. The numbers of subjects listed in Table III.2 exclude patients
with missing outcomes, except for analyses where missing outcomes were
changed to failures.

+------------------+---+----------+-----+--------------+--------------+
| **Table III.2.** |   |          |     |              |              |
| FDA Analysis of  |   |          |     |              |              |
| Clinical Outcome |   |          |     |              |              |
| in Study 51      |   |          |     |              |              |
| (inv             |   |          |     |              |              |
| estigator-blind) |   |          |     |              |              |
+------------------+---+----------+-----+--------------+--------------+
| **FDA-Defined**  | * |          | **C |              | **95%        |
|                  | * |          | efp |              | Confidence   |
| **Study          | L |          | odo |              | Interval**   |
| Population**     | i |          | xim |              |              |
|                  | n |          | e** |              |              |
|                  | e |          |     |              |              |
|                  | z |          |     |              |              |
|                  | o |          |     |              |              |
|                  | l |          |     |              |              |
|                  | i |          |     |              |              |
|                  | d |          |     |              |              |
|                  | * |          |     |              |              |
|                  | * |          |     |              |              |
+------------------+---+----------+-----+--------------+--------------+
|                  | * | *        | **  | **Success    |              |
|                  | * | *Success | N** | Rates (%)**  |              |
|                  | N | Rates    |     |              |              |
|                  | * | (%)**    |     |              |              |
|                  | * |          |     |              |              |
+------------------+---+----------+-----+--------------+--------------+
| ITT              | 2 | 82.8     | 222 | 86.5         | (-10.8, 3.4) |
|                  | 2 |          |     |              |              |
|                  | 7 |          |     |              |              |
+------------------+---+----------+-----+--------------+--------------+
| ITT (missing as  | 2 | 69.1     | 268 | 71.6         | (-10.6, 5.5) |
| failure)         | 7 |          |     |              |              |
|                  | 2 |          |     |              |              |
+------------------+---+----------+-----+--------------+--------------+
| MITT             | 5 | 85.2     | 52  | 80.8         | (-11.8,      |
|                  | 4 |          |     |              | 20.6)        |
+------------------+---+----------+-----+--------------+--------------+
| MITT (missing as | 6 | 76.7     | 60  | 70.0         | (-10.8,      |
| failure)         | 0 |          |     |              | 24.1)        |
+------------------+---+----------+-----+--------------+--------------+
| FDA CE           | 2 | 84.5     | 208 | 89.9         | (-12.2, 1.4) |
|                  | 1 |          |     |              |              |
|                  | 3 |          |     |              |              |
+------------------+---+----------+-----+--------------+--------------+
| FDA ME           | 5 | 88.0     | 48  | 81.3         | (-9.5, 23.0) |
|                  | 0 |          |     |              |              |
+------------------+---+----------+-----+--------------+--------------+
| FDA bacteremic   | 3 | 100      | 5   | 60.0         |              |
| ME               |   |          |     |              |              |
+------------------+---+----------+-----+--------------+--------------+

Response rates in the FDA analysis were lower for both treatment arms
than in the sponsor's analyses. The 95% confidence intervals around the
difference in response rates between treatment arms were similar in both
the FDA analysis and the sponsor's analysis of ITT and MITT populations.

Analyses that counted patients with missing outcomes as failures yielded
lower response rates, as expected. These analyses should be interpreted
with caution, since there were a significant number of patients with
missing outcomes, and many of these patients may not have been true
therapeutic failures.

[Nosocomial Pneumonia]{.underline}

Pharmacia & Upjohn conducted one study of nosocomial pneumonia (Study
48A). Study 48 was a randomized, double-blind trial in patients with
nosocomially-acquired pneumonia. It compared IV linezolid 600 mg q12h
with IV vancomycin 1 g q12h. Patients in both arms could receive
aztreonam if Gram-negative pathogens were identified. Details of the
study design can be found in Pharmacia & Upjohn's briefing package.

Table III.3 shows results of the FDA analysis of clinical outcome in
Study 48A. The methods used by FDA reviewers to determine clinical
success rates are described in the Appendix. A total of 203 linezolid
subjects and 193 comparator subjects received at least one dose of study
drug. The numbers of subjects listed in Table III.3 exclude patients
with missing outcomes, except for analyses where missing outcomes were
changed to failures.

  ------------------ --------------- ----------- ---------------- -------------- --------------
  **Table III.3.**                                                               
  FDA Analysis of                                                                
  Clinical Outcome                                                               
  in Study 48A                                                                   

  **FDA-Defined      **Linezolid**               **Vancomycin**                  **95%
  Study Population**                                                             Confidence
                                                                                 Interval**

                     **N**           **Success   **N**            **Success      
                                     Rates (%)**                  Rates (%)**    

  ITT                174             48.9        164              44.5           (-6.9, 15.6)

  ITT (missing as    203             41.9        193              37.8           (-6.1, 14.2)
  failure)                                                                       

  MITT               82              57.3        72               45.8           (-5.5, 28.5)

  MITT (missing as   94              50.0        83               39.8           (-5.5, 26.0)
  failure)                                                                       

  FDA CE             122             57.4        103              60.2           (-16.6, 11.0)

  FDA ME             54              66.7        41               63.4           (-18.3, 24.8)

  FDA bacteremic ME  4               50.0        6                66.7           

  FDA VAP CE         59              40.7        51               37.3           (-16.7, 23.5)
  ------------------ --------------- ----------- ---------------- -------------- --------------

VAP, ventilator-associated pneumonia

Response rates in the FDA analysis were somewhat lower for both
treatment arms than in the sponsor's analyses. The 95% confidence
intervals around the difference in response rates between treatment arms
were similar in both the FDA analysis and the sponsor's analysis.

Analyses that counted patients with missing outcomes as failures yielded
lower response rates, as expected. These analyses should be interpreted
with caution, since there were a significant number of patients with
missing outcomes, and many of these patients may not have been true
therapeutic failures.

There was a lower all-cause mortality rate in the linezolid arm than in
the vancomycin arm (17.7% v. 25.4%, p=0.067, Fisher's exact test). The
rate of mortality due to the initial infection was also lower in the
linezolid arm than in the vancomycin arm (5.4% v. 8.8%, p=0.24, Fisher's
exact test).

**[Uncomplicated Skin and Skin Structure Infections]{.underline}**

Originally, the sponsor proposed one multi-national study of
uncomplicated skin and skin structure infections. This was a randomized,
double-blind trial comparing linezolid 400 mg PO BID with clarithromycin
250 mg PO BID. When sites in the United States, Canada, and Mexico
achieved their target enrollment, the study was split into a North
American trial (Study 39A) and a supportive trial of non-North American
sites (Study 39). Study 39A was submitted as the pivotal trial for
uncomplicated skin and skin structure infections. Details of the study
design can be found in Pharmacia & Upjohn's briefing package.

Table III.4 shows results of the FDA analysis of clinical outcome in
studies 39A and 39. The methods used by FDA reviewers to determine
clinical success rates are described in the Appendix. A total of 382
linezolid subjects and 371 clarithromycin subjects received at least one
dose of study medication in Study 39A. In Study 39, there were 166
subjects who received at least one dose of study medication in both
study arms. It should be noted that 10-15% of ITT subjects have missing
outcomes, adding uncertainty to the interpretation of study results. The
numbers of subjects listed in the FDA analysis table exclude patients
with missing outcomes except where missing outcomes were changed to
failures.

+-----------------+----+------------+----+------------+--------------+
| **Table         |    |            |    |            |              |
| III.4.** FDA    |    |            |    |            |              |
| Analysis of     |    |            |    |            |              |
| Clinical        |    |            |    |            |              |
| Outcome in      |    |            |    |            |              |
| Studies 39A and |    |            |    |            |              |
| 39              |    |            |    |            |              |
+-----------------+----+------------+----+------------+--------------+
| **FDA-Defined** | *  |            | ** |            | **95%        |
|                 | *L |            | Cl |            | Confidence   |
| **Study         | in |            | ar |            | Interval**   |
| Population**    | ez |            | it |            |              |
|                 | ol |            | hr |            |              |
|                 | id |            | om |            |              |
|                 | ** |            | yc |            |              |
|                 |    |            | in |            |              |
|                 |    |            | ** |            |              |
+-----------------+----+------------+----+------------+--------------+
|                 | *  | **Success  | *  | **Success  |              |
|                 | *N | Rates      | *N | Rates      |              |
|                 | ** | (%)**      | ** | (%)**      |              |
+-----------------+----+------------+----+------------+--------------+
| ## Pi           |    |            |    |            |              |
| votal Study 39A |    |            |    |            |              |
+-----------------+----+------------+----+------------+--------------+
| ITT             | 3  | 85.9       | 3  | 83.5       | (-3.4, 8.2)  |
|                 | 41 |            | 22 |            |              |
+-----------------+----+------------+----+------------+--------------+
| ITT (missing as | 3  | 76.7       | 3  | 72.5       | (-2.3, 10.7) |
| failure)        | 82 |            | 71 |            |              |
+-----------------+----+------------+----+------------+--------------+
| FDA CE          | 3  | 88.4       | 3  | 85.3       | (-2.5, 8.7)  |
|                 | 20 |            | 07 |            |              |
+-----------------+----+------------+----+------------+--------------+
| FDA ME          | 1  | 88.0       | 1  | 83.5       | (-5.4, 14.4) |
|                 | 08 |            | 21 |            |              |
+-----------------+----+------------+----+------------+--------------+
| ## Supp         |    |            |    |            |              |
| ortive Study 39 |    |            |    |            |              |
+-----------------+----+------------+----+------------+--------------+
| ITT             | 1  | 87.8       | 1  | 91.3       | (-11.1, 4.2) |
|                 | 48 |            | 49 |            |              |
+-----------------+----+------------+----+------------+--------------+
| FDA CE          | 1  | 89.0       | 1  | 89.8       | (-9.2, 7.6)  |
|                 | 27 |            | 27 |            |              |
+-----------------+----+------------+----+------------+--------------+
| FDA ME          | 43 | 95.3       | 60 | 96.7       | (-11.1, 8.4) |
+-----------------+----+------------+----+------------+--------------+

The FDA analysis focused on the ITT population. Clinical success rates
determined using the FDA algorithm are similar in the linezolid and
clarithromycin groups. Success rates decreased when subjects with
missing outcomes are included as failures, but the results are still
similar across the two study arms. The FDA clinically evaluable
population differs from the ITT population mainly due to study drug
compliance. The FDA microbiologically evaluable population consists of
clinically evaluable subjects with one of the following baseline
pathogens: *Staphylococcus aureus*, *Streptococcus pyogenes*,
*Streptococcus agalactiae*, *Enterococcus faecium,* or *Enterococcus
faecalis*. This microbiologically evaluable population is smaller than
that given by the sponsor. Overall, the clinical success rates are
comparable in the linezolid and clarithromycin groups. The FDA analyses
are consistent with the sponsor's study results.

Analyses that counted patients with missing outcomes as failures yielded
lower response rates, as expected. These analyses should be interpreted
with caution, since there were a significant number of patients with
missing outcomes, and many of these patients may not have been true
therapeutic failures.

[Complicated Skin and Skin Structure Infections]{.underline}

Pharmacia & Upjohn conducted one study of complicated skin and skin
structure infections (Study 55). This was a randomized, double-blind
trial comparing the use of IV/PO linezolid 600 mg q12h with IV oxacillin
2 g QID /PO dicloxacillin 500 mg q6h. Details of the study design can be
found in Pharmacia & Upjohn's briefing package.

Table III.5 shows results of the FDA analysis of clinical outcome in
Study 55. The methods used by FDA reviewers to determine clinical
success rates are described in the Appendix. A total of 400 linezolid
subjects and 419 comparator subjects received at least one dose of study
drug. In this trial, 15-20% of ITT subjects had missing outcomes, adding
uncertainty to the interpretation of results. The numbers of subjects
listed in Table III.5 exclude patients with missing outcomes, except for
analyses where missing outcomes were changed to failures.

+-----------------+---+------------+-----+------------+--------------+
| **Table         |   |            |     |            |              |
| III.5.** FDA    |   |            |     |            |              |
| Analysis of     |   |            |     |            |              |
| Clinical        |   |            |     |            |              |
| Outcome in      |   |            |     |            |              |
| Study 55        |   |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| **FDA-Defined** | * |            | **O |            | **95%        |
|                 | * |            | xac |            | Confidence   |
| **Study         | L |            | ill |            | Interval**   |
| Population**    | i |            | in/ |            |              |
|                 | n |            | Dic |            |              |
|                 | e |            | lox |            |              |
|                 | z |            | aci |            |              |
|                 | o |            | lli |            |              |
|                 | l |            | n** |            |              |
|                 | i |            |     |            |              |
|                 | d |            |     |            |              |
|                 | * |            |     |            |              |
|                 | * |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
|                 | * | **Success  | **  | **Success  |              |
|                 | * | Rates      | N** | Rates      |              |
|                 | N | (%)**      |     | (%)**      |              |
|                 | * |            |     |            |              |
|                 | * |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| ITT             | 3 | 85.0       | 348 | 78.7       | ( 0.2, 12.4) |
|                 | 2 |            |     |            |              |
|                 | 7 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| ITT (missing as | 4 | 69.5       | 419 | 65.4       | (-2.5, 10.8) |
| failure)        | 0 |            |     |            |              |
|                 | 0 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| ITT-prime       | 2 | 86.2       | 267 | 82.0       | (-2.3, 10.8) |
|                 | 6 |            |     |            |              |
|                 | 9 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| ITT-prime       | 3 | 73.4       | 313 | 70.0       | (-3.9, 10.8) |
| (missing as     | 1 |            |     |            |              |
| failure)        | 6 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| FDA CE          | 2 | 89.8       | 242 | 85.1       | (-1.6, 11.0) |
|                 | 4 |            |     |            |              |
|                 | 5 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| FDA ME          | 1 | 85.1       | 108 | 82.4       | (-8.2, 13.7) |
|                 | 0 |            |     |            |              |
|                 | 1 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+

The FDA analysis focused on the ITT-prime population. This population
represents the subgroup of ITT subjects based on certain baseline
criteria of the study. One of the inclusion criteria for this trial
specified that subjects should have one of the following: fever, white
blood cell count \>10,000, or bands \>15%. This criterion was used to
include subjects with a systemic response to infection as a means of
selecting subjects with truly complicated infections. The decrease in
the number of subjects in the ITT-prime group (compared to the ITT) is
mainly due to application of this baseline criterion. The clinical
success rates for the two groups are similar. Similar success rates are
also seen when all subjects with missing outcomes are included as
failures.

The FDA clinically evaluable population is the subgroup of ITT-prime
subjects who met certain post-baseline requirements. The main reason for
the decrease in the number of patients included is related to a
requirement for study drug compliance. The microbiologically evaluable
population is smaller than that given by the sponsor. As with the
uncomplicated skin and skin structure infection trial, the FDA
microbiologically evaluable population is the subgroup of clinically
evaluable subjects who had at least one of the following organisms on
baseline culture: *Staphylococcus aureus*, *Streptococcus pyogenes*,
*Streptococcus agalactiae*, *Enterococcus faecium,* or *Enterococcus
faecalis*. Overall, the clinical success rates for linezolid are similar
to the success rates for the comparator in the populations analyzed.

# Analyses that counted patients with missing outcomes as failures yielded lower response rates, as expected. These analyses should be interpreted with caution, since there were a significant number of patients with missing outcomes, and many of these patients may not have been true therapeutic failures. 

# Infections due to methicillin-resistant staphylococcal species

Pharmacia & Upjohn conducted one study of infections due to
methicillin-resistant staphylococcal species (Study 31). This was a
randomized, open-label trial comparing the use of IV/PO linezolid 600 mg
q12h with IV vancomycin 1 g q12h. A third arm enrolled patients who
received IV vancomycin q12h followed by PO linezolid q12h; this arm was
discontinued after 51 patients had been enrolled. Data on these patients
is not included in the analysis. Details of the study design can be
found in Pharmacia & Upjohn's briefing package.

Table III.6 shows results of the FDA analysis of clinical outcomes in
Study 31. The methods used by FDA reviewers to determine clinical
success rates are described in the Appendix. A total of 240 linezolid
subjects and 220 comparator subjects received at least one dose of study
drug. The numbers of subjects listed in Table III.6 exclude patients
with missing outcomes, except for analyses where missing outcomes were
changed to failures.

+-----------------+---+------------+-----+------------+--------------+
| **Table         |   |            |     |            |              |
| III.6.** FDA    |   |            |     |            |              |
| Analysis of     |   |            |     |            |              |
| Clinical        |   |            |     |            |              |
| Outcome in      |   |            |     |            |              |
| Study 31        |   |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| **FDA-Defined** | * |            | **  |            | **95%        |
|                 | * |            | Van |            | Confidence   |
| **Study         | L |            | com |            | Interval**   |
| Population**    | i |            | yci |            |              |
|                 | n |            | n** |            |              |
|                 | e |            |     |            |              |
|                 | z |            |     |            |              |
|                 | o |            |     |            |              |
|                 | l |            |     |            |              |
|                 | i |            |     |            |              |
|                 | d |            |     |            |              |
|                 | * |            |     |            |              |
|                 | * |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
|                 | * | **Success  | **  | **Success  |              |
|                 | * | Rates      | N** | Rates      |              |
|                 | N | (%)**      |     | (%)**      |              |
|                 | * |            |     |            |              |
|                 | * |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| ITT             | 1 | 61.3       | 160 | 63.1       | (-12.7, 9.1) |
|                 | 8 |            |     |            |              |
|                 | 1 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| ITT (missing as | 2 | 46.3       | 220 | 45.9       | (-9.2, 9.9)  |
| failure)        | 4 |            |     |            |              |
|                 | 0 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| MITT            | 1 | 58.6       | 112 | 66.1       | (-20.5, 5.6) |
|                 | 2 |            |     |            |              |
|                 | 8 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| MITT (missing   | 1 | 47.8       | 144 | 51.4       | (-15.6, 8.3) |
| as failure)     | 5 |            |     |            |              |
|                 | 7 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| FDA CE          | 1 | 80.2       | 125 | 72.0       | (-3.4, 19.7) |
|                 | 1 |            |     |            |              |
|                 | 6 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| FDA ME          | 5 | 76.3       | 67  | 71.6       | (-12.3,      |
|                 | 9 |            |     |            | 21.5)        |
+-----------------+---+------------+-----+------------+--------------+
| FDA bacteremic  | 1 | 58.8       | 14  | 71.4       |              |
| ME              | 7 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+

Overall, the clinical success rates for linezolid are comparable to the
success rates for the comparator in the populations analyzed. The FDA
analysis is, in general, consistent with the sponsor's analysis,
although the FDA analysis of the MITT population showed a different
lower bound for the 95% confidence interval (FDA: -20.5; sponsor:
-11.4).

Analyses that counted patients with missing outcomes as failures yielded
lower response rates, as expected. These analyses should be interpreted
with caution, since there were a significant number of patients with
missing outcomes, and many of these patients may not have been true
therapeutic failures.

Table III.7 shows results of the FDA analysis of clinical outcome in
Study 31 by site of infection for the clinically evaluable population
with MRSA infection.

+--------------------------+------+--------------+-----+--------------+
| **Table III.7.** FDA     |      |              |     |              |
| Analysis of Clinical     |      |              |     |              |
| Outcome in Study 31 by   |      |              |     |              |
| site of MRSA infection   |      |              |     |              |
+--------------------------+------+--------------+-----+--------------+
| **MRSA Infection Site**  | *    |              | **  |              |
|                          | *Lin |              | Van |              |
|                          | ezol |              | com |              |
|                          | id** |              | yci |              |
|                          |      |              | n** |              |
+--------------------------+------+--------------+-----+--------------+
|                          | *    | **Success    | **  | **Success    |
|                          | *N** | Rates (%)**  | N** | Rates (%)**  |
+--------------------------+------+--------------+-----+--------------+
| All sources              | 62   | 79.0         | 69  | 72.5         |
+--------------------------+------+--------------+-----+--------------+
| Pneumonia                | 11   | 90.9         | 17  | 70.6         |
|                          |      |              |     |              |
| \- with bacteremia       | 3    | 100.0        | 3   | 66.7         |
+--------------------------+------+--------------+-----+--------------+
| SSTI                     | 38   | 81.6         | 41  | 75.6         |
|                          |      |              |     |              |
| \- with bacteremia       | 5    | 60.0         | 3   | 100.0        |
+--------------------------+------+--------------+-----+--------------+
| UTI                      | 2    | 100.0        | 1   | 100.0        |
+--------------------------+------+--------------+-----+--------------+
| Other                    | 9    | 44.4         | 6   | 50.0         |
|                          |      |              |     |              |
| \- with bacteremia       | 3    | 33.3         | 5   | 60.0         |
+--------------------------+------+--------------+-----+--------------+
| Bacteremia of unknown    | 2    | 100.0        | 3   | 66.7         |
| origin                   |      |              |     |              |
+--------------------------+------+--------------+-----+--------------+

#  Infections due to vancomycin-resistant enterococci

Pharmacia & Upjohn conducted one study of infections due to
vancomycin-resistant enterococci (Study 54A). This was a randomized,
double-blind, dose-response trial designed to demonstrate the
superiority of linezolid 600 mg q12h over linezolid 200 mg q12h. The
sponsor also submitted supportive data from an ongoing continuation of
this study, designated Study 54. Details of the study design can be
found in Pharmacia & Upjohn's briefing package.

Table III.8 shows results of the FDA analysis of clinical outcome in
Study 54A. The methods used by FDA reviewers to determine clinical
success rates are described in the Appendix. A total of 79 treated
subjects were randomized to the 600-mg arm and 66 to the 200-mg arm. The
FDA analysis focused on the subset of patients who had VRE isolated from
a valid culture source at baseline (MITT-VRE). Results with patients
with bacteremia are also provided, as this was a key subgroup of
interest, specified in the protocol. The numbers of subjects listed in
Table III.7 exclude patients with missing outcomes, except for analyses
where missing outcomes were changed to failures.

+-----------------+---+------------+-----+------------+--------------+
| **Table         |   |            |     |            |              |
| III.8.** FDA    |   |            |     |            |              |
| Analysis of     |   |            |     |            |              |
| Clinical        |   |            |     |            |              |
| Outcome in      |   |            |     |            |              |
| Study 54A       |   |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| **FDA-Defined** | * |            | **  |            | **p value**  |
|                 | * |            | Lin |            |              |
| **Study         | L |            | ezo |            | **(Fisher's  |
| Population**    | i |            | lid |            | exact        |
|                 | n |            | 200 |            | test)**      |
|                 | e |            | m   |            |              |
|                 | z |            | g** |            |              |
|                 | o |            |     |            |              |
|                 | l |            |     |            |              |
|                 | i |            |     |            |              |
|                 | d |            |     |            |              |
|                 | 6 |            |     |            |              |
|                 | 0 |            |     |            |              |
|                 | 0 |            |     |            |              |
|                 | m |            |     |            |              |
|                 | g |            |     |            |              |
|                 | * |            |     |            |              |
|                 | * |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
|                 | * | **Success  | **  | **Success  |              |
|                 | * | Rates      | N** | Rates      |              |
|                 | N | (%)**      |     | (%)**      |              |
|                 | * |            |     |            |              |
|                 | * |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| MITT-VRE        | 5 | 67.2       | 46  | 52.2       | 0.158        |
|                 | 8 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| MITT-VRE        | 6 | 60.0       | 52  | 46.2       | 0.142        |
| (missing as     | 5 |            |     |            |              |
| failure)        |   |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| Bacteremic      | 1 | 58.8       | 14  | 28.6       | 0.149        |
| MITT-VRE        | 7 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| Bacteremic      | 1 | 55.6       | 16  | 25.0       | 0.092        |
| MITT-VRE        | 8 |            |     |            |              |
| (missing as     |   |            |     |            |              |
| failure)        |   |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+

Analyses that counted patients with missing outcomes as failures yielded
lower response rates, as expected. All of these analyses should be
interpreted with caution, since there were a number of patients with
missing outcomes, and many of these patients may not have been true
therapeutic failures.

Table III.9 shows the FDA analysis of clinical outcome for the MITT-VRE
population, broken down by site of infection. Infections labeled as
"Other" consisted primarily of complicated intra-abdominal infections.
The numbers of subjects listed in Table III.8 exclude patients with
missing outcomes. Sensitivity analyses treating patients with missing
outcomes as failures gave lower response rates but were generally
comparable. Since no adjustment has been made for multiple comparisons,
these results should be viewed cautiously.

+-----------------+---+------------+-----+------------+--------------+
| **Table         |   |            |     |            |              |
| III.9.** FDA    |   |            |     |            |              |
| Analysis of     |   |            |     |            |              |
| Clinical        |   |            |     |            |              |
| Outcome in      |   |            |     |            |              |
| Study 54A by    |   |            |     |            |              |
| site of         |   |            |     |            |              |
| infection       |   |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| **FDA-Defined** | * |            | **  |            | **p value**  |
|                 | * |            | Lin |            |              |
| **Study         | L |            | ezo |            | **(Fisher's  |
| Population**    | i |            | lid |            | exact        |
|                 | n |            | 200 |            | test)**      |
|                 | e |            | m   |            |              |
|                 | z |            | g** |            |              |
|                 | o |            |     |            |              |
|                 | l |            |     |            |              |
|                 | i |            |     |            |              |
|                 | d |            |     |            |              |
|                 | 6 |            |     |            |              |
|                 | 0 |            |     |            |              |
|                 | 0 |            |     |            |              |
|                 | m |            |     |            |              |
|                 | g |            |     |            |              |
|                 | * |            |     |            |              |
|                 | * |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
|                 | * | **Success  | **  | **Success  |              |
|                 | * | Rates      | N** | Rates      |              |
|                 | N | (%)**      |     | (%)**      |              |
|                 | * |            |     |            |              |
|                 | * |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| MITT-VRE (all)  | 5 | 67.2       | 46  | 52.2       | 0.158        |
|                 | 8 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| Bacteremia of   | 1 | 50.0       | 7   | 28.6       | 0.622        |
| unknown origin  | 0 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| Skin/skin       | 1 | 69.2       | 5   | 100.0      | 0.278        |
| structure       | 3 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| Urinary tract   | 1 | 63.2       | 20  | 60.0       | 1.000        |
| infection       | 9 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| Pneumonia       | 3 | 66.7       | 1   | 0.0        | 1.000        |
+-----------------+---+------------+-----+------------+--------------+
| Other           | 1 | 84.6       | 13  | 38.5       | 0.041        |
|                 | 3 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+

Table III.10 shows all-cause mortality rates for the MITT-VRE
population, and for MITT-VRE patients with bacteremia at baseline.

+-----------------+---+------------+-----+------------+--------------+
| **Table         |   |            |     |            |              |
| III.10.** FDA   |   |            |     |            |              |
| Analysis of     |   |            |     |            |              |
| Mortality Rates |   |            |     |            |              |
| in Study 54A    |   |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| **FDA-Defined** | * |            | **  |            | **p value**  |
|                 | * |            | Lin |            |              |
| **Study         | L |            | ezo |            | **(Fisher's  |
| Population**    | i |            | lid |            | exact        |
|                 | n |            | 200 |            | test)**      |
|                 | e |            | m   |            |              |
|                 | z |            | g** |            |              |
|                 | o |            |     |            |              |
|                 | l |            |     |            |              |
|                 | i |            |     |            |              |
|                 | d |            |     |            |              |
|                 | 6 |            |     |            |              |
|                 | 0 |            |     |            |              |
|                 | 0 |            |     |            |              |
|                 | m |            |     |            |              |
|                 | g |            |     |            |              |
|                 | * |            |     |            |              |
|                 | * |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
|                 | * | *          | **  | *          |              |
|                 | * | *Mortality | N** | *Mortality |              |
|                 | N | Rate (%)** |     | Rate (%)** |              |
|                 | * |            |     |            |              |
|                 | * |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| MITT-VRE        | 6 | 24.6       | 52  | 34.6       | 0.306        |
|                 | 5 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| Bacteremic      | 1 | 22.2       | 16  | 56.3       | 0.076        |
| MITT-VRE        | 8 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+

In June 1999, the sponsor made a blinded decision to regard patients
already randomized to Study 54 as comprising a stand-alone trial for
submission, designated Study 54A. Thus, with this decision, the sponsor
has opted to "spend all alpha" on Study 54A. However, data from 82
patients from Study 54 have been submitted and reviewed. It is not clear
how to utilize information from Study 54 to support Study 54A results
without compromising the integrity of the statistical inference.
Employing information from Study 54 to augment Study 54A, even
informally, might roughly correspond to giving a trial two opportunities
to demonstrate a statistically significant result, without an
appropriate statistical adjustment. Results from the FDA analysis of the
82 patients from Study 54 are presented in Table III.11.

+-----------------+---+------------+-----+------------+--------------+
| **Table         |   |            |     |            |              |
| III.11.** FDA   |   |            |     |            |              |
| Analysis of     |   |            |     |            |              |
| Clinical        |   |            |     |            |              |
| Outcome in      |   |            |     |            |              |
| Study 54        |   |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| **FDA-Defined** | * |            | **  |            | **p value**  |
|                 | * |            | Lin |            |              |
| **Study         | L |            | ezo |            | **(Fisher's  |
| Population**    | i |            | lid |            | exact        |
|                 | n |            | 200 |            | test)**      |
|                 | e |            | m   |            |              |
|                 | z |            | g** |            |              |
|                 | o |            |     |            |              |
|                 | l |            |     |            |              |
|                 | i |            |     |            |              |
|                 | d |            |     |            |              |
|                 | 6 |            |     |            |              |
|                 | 0 |            |     |            |              |
|                 | 0 |            |     |            |              |
|                 | m |            |     |            |              |
|                 | g |            |     |            |              |
|                 | * |            |     |            |              |
|                 | * |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
|                 | * | **Success  | **  | **Success  |              |
|                 | * | Rates      | N** | Rates      |              |
|                 | N | (%)**      |     | (%)**      |              |
|                 | * |            |     |            |              |
|                 | * |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| MITT-VRE        | 2 | 64.3       | 35  | 48.6       | 0.308        |
|                 | 8 |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+
| MITT-VRE        | 3 | 60.0       | 41  | 41.5       | 0.153        |
| (missing as     | 0 |            |     |            |              |
| failure)        |   |            |     |            |              |
+-----------------+---+------------+-----+------------+--------------+

# IV. Appendix

# Clinical Trial Review Methods

#### Efficacy analysis

#### *Material analyzed*

Table A.1 shows the pivotal and supportive phase III trials analyzed in
the FDA review.

  ----------------------------------------------------------------------------------------
  **Table A.1.**                                                               
  Phase III                                                                    
  trials reviewed                                                              
  --------------- ---------------------- --------------- --------------------- -----------
  **Study \#**    **Indication           **Linezolid     **Comparator**        **Treated
                  (design)**             Formulation**                         pts**

  M/1260/0033     CAP (open-label)       IV, PO          Ceftriaxone           747
  (**pivotal**)                                          IV/Cefpodoxime PO     

  M/1260/0051     CAP                    PO              Cefpodoxime PO        540
  (**pivotal**)   (investigator-blind)                                         

  M/1260/0048A    HAP (double-blind)     IV              Vancomycin IV         396
  (**pivotal**)                                                                

  M/1260/0039A    uSSSI (double-blind)   PO              Clarithromycin        753
  (**pivotal**)                                                                

  M/1260/0039     uSSSI (double-blind)   PO              Clarithromycin        332

  M/1260/0055     cSSSI (double-blind)   IV, PO          Oxacillin             819
  (**pivotal**)                                          IV/Dicloxacillin PO   

  M/1260/0031     MRSS infection         IV, PO          Vancomycin IV         460

  M/1260/0054A    VRE infection          IV, PO          Dose comparison; 600  145
  (**pivotal**)   (double-blind)                         mg v. 200 mg          

  M/1260/0054     VRE infection          IV, PO          Dose comparison; 600  82
                  (double-blind)                         mg v. 200 mg          
  ----------------------------------------------------------------------------------------

#### *Definition of analytic populations and outcomes*

#### FDA reviewers generally used the same evaluability criteria as the sponsor for constructing ITT, modified ITT (MITT), clinically evaluable (CE), and microbiologically evaluable (ME) populations. However, in the FDA analysis, patients who were discontinued from therapy for lack of efficacy were generally considered clinically evaluable if they received at least four doses of study drug; such patients were not necessarily clinically evaluable in the sponsor's analysis. In addition, in the FDA analysis, patients who died of their initial infection before follow-up were generally considered clinically evaluable; such patients were generally excluded from the sponsor's clinically evaluable population. Patients with missing clinical outcomes were excluded from the FDA CE populations.

#### For individual studies, additional MITT populations were constructed for the FDA review:

1)  ITT**-**prime: For the study on complicated skin and soft tissue
    infections (Study 55), this population included all ITT patients who
    met baseline inclusion criteria.

2)  MITT-VRE -- This population was constructed for Studies 54A and 54,
    and included all ITT patients who had vancomycin-resistant
    enterococci isolated from a valid culture source at baseline.

FDA reviewers used the same definitions of clinical cure and failure as
the investigators. However, the algorithm used for determining clinical
outcome differed between the FDA and the sponsor.

#### *Differences between FDA's and sponsor's analytic methodology*

Both the FDA's and sponsor's analyses started with the test-of cure
(TOC) efficacy assessments. However, the FDA's and sponsor's decision
rules for classifying outcomes differed, primarily in the treatment of
patients with missing investigator assessments. This was particularly
true for those subjects who had missing assessments because they died
prior to the test-of-cure (TOC) visit.

Thus, the two approaches differ mainly in how outcomes of failure and
missing were defined. Consequently, there was little difference between
the FDA and sponsor for those ITT analyses that counted missing values
as failures.

The tables below describe the algorithms and these differences in
detail. The outcomes shown apply to the ITT population. The FDA
algorithm did not distinguish between indeterminate and missing
outcomes, regarding indeterminate outcomes as missing. Patients who had
an outcome of missing were not included in the FDA analysis of the CE
population.

**Step 1.** Both approaches start with the investigator's assessment at
TOC. However, if the investigator's TOC assessment was missing or
indeterminate, the two approaches differed:

+-----------------------------------+---------------------+-----------+
| ## If investigator assessment was | Sponsor-defined     | FDA       |
|  missing or indeterminate at TOC: | outcome             | outcome   |
+-----------------------------------+---------------------+-----------+
| Missing or indeterminate at EOT   | Failure             | Missing   |
| and alive at follow-up            |                     |           |
+-----------------------------------+---------------------+-----------+
| Missing or indeterminate at EOT   | Failure             | Failure   |
| and dead at follow-up             |                     |           |
+-----------------------------------+---------------------+-----------+
| Improved or cure at EOT and alive | Indeterminate       | Missing   |
| at follow-up                      |                     |           |
+-----------------------------------+---------------------+-----------+
| Improved or cure at EOT and dead  | Indeterminate       | Failure   |
| at follow-up                      |                     |           |
+-----------------------------------+---------------------+-----------+
| Failure at EOT                    | Failure             | Failure   |
+-----------------------------------+---------------------+-----------+

**Step 2.** Revise outcome if there was evidence of lack of efficacy

+-----------------------------------+---------------------+-----------+
| ## Evidence of lack of efficacy   | Sponsor-defined     | FDA       |
|                                   | outcome             | outcome   |
+-----------------------------------+---------------------+-----------+
| New antibiotic given for lack of  | Failure             | Failure   |
| efficacy                          |                     |           |
+-----------------------------------+---------------------+-----------+
| Investigator stated patient       | Generally failure   | Failure   |
| discontinued from study due to    |                     |           |
| lack of efficacy                  |                     |           |
+-----------------------------------+---------------------+-----------+

**Step 3.** Revise outcome if duration of drug exposure was too short

+-----------------------------------+---------------------+-----------+
| ## Study drug exposure            | Sponsor Outcome     | FDA       |
|                                   |                     | Outcome   |
+-----------------------------------+---------------------+-----------+
| Investigator TOC assessment was   | Missing             | Failure   |
| failure and drug use \< 2 days or |                     |           |
| 4 doses                           |                     |           |
+-----------------------------------+---------------------+-----------+
| Investigator TOC assessment was   | Missing             | Cure      |
| cure and drug use \< 5 days or 10 |                     |           |
| doses                             |                     |           |
+-----------------------------------+---------------------+-----------+

#### *Review of evaluability and outcome assessments*

All of the pivotal and supportive phase III trials were reviewed using
the algorithms described above. Random sampling of patient data was used
for all studies, except for studies 54A and 54 (VRE trials); for these
studies, data from all patients was examined. For each of the other
trials, the statistical reviewer generated a random sample of enrolled
patients. The medical reviewers assessed the evaluability and clinical
outcome of patients in these samples. These assessments were performed
using scanned images of case report forms (CRFs) and electronic datasets
as source data. Reviewers were blinded to treatment group assignment.

For each patient examined, the medical reviewer determined whether they
should be included in a particular analytic population (i.e., were
evaluable for purposes of ITT, MITT, CE, or ME analysis), and assessed
their clinical and microbiologic outcome at TOC. Patients who died
before the end of follow-up were considered to have died from the
initial infection if either of the following conditions were met:

-   the investigator indicated that the initial infection was the cause
    of death,

or

-   the investigator-supplied cause of death directly indicated an
    ongoing infectious process (e.g., 'septic shock') and clinical
    observations were consistent with persistence or progression of the
    original infection. In the case of infections due to VRE,
    attribution of death to the initial infection also required
    isolation of the original pathogen from a normally sterile body site
    or fluid (e.g., blood).

The reviewer's outcome and evaluability assessments for patients in the
random sample were then compared with those generated using the
investigators' assessments, modified by the FDA algorithm as described
above. Discrepancies were identified, the reasons for discrepancies were
determined, and the assessments were reconciled if possible. Since the
number of discrepancies was sufficiently low, the investigator results
(modified by the FDA algorithm) were accepted as valid in all trials
except for 54A and 54 (the VRE infection studies). The results were then
used to generate response rates, confidence intervals around the
differences in response rates between treatment arms, and p values where
appropriate.

[Safety analysis]{.underline}

*[Material analyzed]{.underline}*

Data from patients in phase II and phase III trials who had received at
least one dose of study medication were examined. The primary sources
for data analysis were electronic datasets supplied by the sponsor;
these contained data on deaths, adverse events, and laboratory results
that had been abstracted from CRFs. Random patient samples were examined
to assess the accuracy of abstraction of data from CRFs to the
electronic datasets.

*[Definitions]{.underline}*

FDA reviewers used the same definitions for adverse events, drug-related
adverse events, serious adverse events (SAEs), and abnormal laboratory
values as the sponsor. Death was attributed to infection using the
criteria described above.

*[Mortality analysis]{.underline}*

All study reports and CRFs summaries of patient deaths were reviewed.
Events were examined for evidence of death due to drug exposure or to
lack of drug efficacy. Mortality rates were determined by treatment
group for specific subgroups of interest.

*[Discontinuations]{.underline}*

All cases of discontinuations due to adverse events were reviewed.
Events were examined for evidence of relation to study drug, or for
evidence of lack of drug efficacy. Discontinuation rates were determined
by treatment group for specific subgroups of interest.

##### Serious adverse events

Serious adverse events were reviewed, including examination of SAEs
representing lack of drug efficacy. SAE rates were determined by
treatment group for specific subgroups of interest.

##### Laboratory values

Laboratory values were plotted to visualize distributions and compared
between treatment groups for specific subgroups of interest. Outliers
were identified and reviewed for evidence of a drug-effect relationship.