Questions to the Committee

December 13, 2000

**NDA 20-726/S-006** **Femara^®^ (letrozole) Tablets**

Novartis Pharmaceuticals Corporation

**Indication**: first-line therapy in postmenopausal women with advanced
breast cancer

One randomized controlled double-blind multinational clinical trial was
conducted in 916 postmenopausal women with hormone receptor positive or
hormone receptor unknown locally advanced (Stage IIIB or locoregional
recurrent disease not amenable to treatment with surgery or radiation)
or advanced metastatic breast cancer comparing Femara 2.5 mg orally once
daily with Tamoxifen 20 mg orally once daily. The safety and efficacy
data are shown in the following Tables.

Table 1 - Efficacy Results per Novartis and per FDA

+--------------+--------+---------+------+--------+--------+------+
|              | ### No |         |      | ##     |        |      |
|              | vartis |         |      | ## FDA |        |      |
+--------------+--------+---------+------+--------+--------+------+
|              | Femara | Tam     | p    | Femara | Tam    | p    |
|              |        |         |      | 453    |        |      |
|              | 453    | 454 pts |      | pts    | 454    |      |
|              | pts    |         |      |        | pts    |      |
+--------------+--------+---------+------+--------+--------+------+
| Response     | 34     | 13 (3%) | 0    | 39     | 14     | 0    |
| Rate         | (8%)   |         | .000 | (9%)   | (3%)   | .000 |
|              |        | 79      | 6^1^ |        |        | 3^1^ |
| CR           | 103    | (17%)   |      | 108    | 84     |      |
|              | (23%)  |         |      | (24%)  | (18%)  |      |
| PR           |        | 92      |      |        |        |      |
|              | 137    | (20%)   |      | 147    | 98     |      |
| Total        | (30%)  |         |      | (32%)  | (21%)  |      |
+--------------+--------+---------+------+--------+--------+------+
| Resp         | 17.0   | 16.5    | Not  | 11.5   | 10.3   | Not  |
| Duration     |        |         | Done |        |        | Done |
| (mo)         |        |         |      |        |        |      |
+--------------+--------+---------+------+--------+--------+------+
| Median TTP   | 9.4    | 6.0     | 0    | 9.87   | 6.15   | 0    |
| (mo)         |        |         | .000 |        |        | .000 |
|              |        |         | 1^2^ |        |        | 1^2^ |
+--------------+--------+---------+------+--------+--------+------+

^1^ Chi Square Test, Two-Sided

^2^ Log Rank test, Two-Sided

Table 2 - Serious AE\'s per FDA

  -------------------------------- ------------------- -------------------
  Toxicity                         Femara (455 pts)    Tamoxifen (455 pts)

  Peripheral thromboembolic events 8 (2%)              11 (2%)

  Cardiovascular events            7 (2%)              4 (1%)

  Cerebrovascular events           5 (1%)              6 (2%)

  Fractures                        21 (5%)             18 (4%)

  Endometrial cancer               0 (0%)              1 (0.2%)

  Ocular toxicity                  7 (2%)              5 (1%)
  -------------------------------- ------------------- -------------------

-   Peripheral thromboembolic events included venous thrombosis,
    thrombophlebitis, portal vein thrombosis and pulmonary embolism.

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-   Cardiovascular events included angina, myocardial infarction,
    myocardial ischemia, and coronary heart disease.

-   Cerebrovascular events included transient ischemic attacks,
    thrombotic or hemorrhagic strokes and development of hemiparesis.

-   Fractures- 21 Femara treated patients had a total of 26 fractures
    compared 18 tamoxifen treated patients who had a total of 20
    fractures. All, or almost all, fractures were disease-related.

At the June 1999 meeting, the Committee indicated that for approval of
new cytotoxic drugs for initial treatment of advanced metastatic breast
cancer a favorable effect on survival in randomized controlled trials is
required. The Committee indicated that a favorable effect on time to
tumor progression (TTP) is not adequate for approval. An impressive
improvement in TTP may be adequate for accelerated approval. A modest
improvement in TTP, even if statistically significant, would not be
adequate for accelerated approval. A better tumor response rate is not
adequate for approval.

The rationale is that cytotoxic drugs have been shown to increase
survival. TTP and tumor response rate are not shown to be surrogates for
survival. Also cytotoxic drugs usually have significant toxicity.
Usually only a minority of patients have a tumor response and most of
these are partial responses. TTP effects are usually modest. In the
absence of a favorable effect on survival, it is not clear that a better
TTP or tumor response rate is sufficient to overcome the drug toxicity.

In contrast, the FDA has accepted a favorable effect on tumor response
or TTP in randomized controlled trials as adequate for approval of
hormonal drugs for initial treatment of advanced metastatic breast
cancer. Updated survival data are required at the time of approval, but
demonstration of statistical superiority or non-inferiority of survival
is not required. If survival is trending strongly against the new
hormonal drug, a decision on approval will be delayed until more mature
survival data are available. Mature survival data are not usually
available when Marketing Applications for hormonal drugs are initially
submitted to the FDA.

The rationale is that hormonal drugs have modest toxicity relative to
cytotoxic drugs. A favorable effect on tumor response rate or TTP comes
at a lesser cost in toxicity than with cytotoxic drugs. In addition,
hormonal drugs have not been shown to increase survival in this setting.
Non-inferiority of survival in this setting is considered a safety
endpoint and is not an indication of efficacy. If a new hormonal drug is
shown to increase survival, the FDA will probably require future new
hormonal drugs to demonstrate a favorable effect on survival to gain
marketing approval.

# Questions to the Committee

1.  Does the Committee agree with the FDA's criteria for approval

> of hormonal drugs for initial treatment of advanced metastatic breast
> cancer?

2.  Does the single study comparing Femara with Tamoxifen show that
    Femara is effective for initial hormonal treatment of postmenopausal
    women with hormone receptor positive or hormone receptor unknown
    advanced metastatic breast cancer?

3.  In view of the efficacy, is the safety of Femara adequate ?

4.  Is the Femara sNDA approvable?