**Gastrointestinal Drugs Advisory Committee**

**Questions for NDA 21-597, Serostim for SBS**

1.  The primary endpoint of this study was change in Total IPN volume
    from week 2 to week 6. Pairwise comparisons of results of the
    primary endpoint yielded statistically significant differences
    between the recombinant human growth hormone (rh-GH)-containing arms
    and the control group. Are the findings in the table below
    clinically meaningful? In your response consider the definition of
    the primary endpoint and the duration of study treatment.

    **Changes in Total IPN Volume**

+----------+-----------+----------+-------------+---------------------+
| **Mean   |           |          | *           |                     |
| Change   |           |          | *Difference |                     |
| in Total |           |          | in Total    |                     |
| IPN      |           |          | IPN Volume  |                     |
| Vol.**   |           |          | \[L/wk\]    |                     |
|          |           |          | (p-value)** |                     |
+----------+-----------+----------+-------------+---------------------+
| **Group  | **Group   | **Group  | **Group**   | **Group**           |
| A**      | B**       | C**      |             |                     |
|          |           |          | **B vs C**  | **A vs C**          |
| **rhGH** | **rhGH +  | **GLN**  |             |                     |
|          | GLN**     |          |             |                     |
| **       |           | *        |             |                     |
| (n=16)** | *         | *(n=9)** |             |                     |
|          | *(n=16)** |          |             |                     |
+----------+-----------+----------+-------------+---------------------+
| **-5.9** | **-7.7**  | **-3.8** | **-3.9      | **-2.1 (0.043)**    |
|          |           |          | (\<0.001)** |                     |
+----------+-----------+----------+-------------+---------------------+

**Baseline IPN Requirements:**

**Group A: 10.3 L/wk**

**Group B: 10.5 L/wk**

##### Group C: 13.5 L/wk

2.  Secondary endpoints were change in Total IPN calories and change in
    IPN or lipid frequency. Pairwise comparisons of the results of these
    secondary endpoints yielded statistically significant differences
    between the rh-GH-containing arms and the control group. Are the
    findings in the table below clinically meaningful?

###### Secondary Efficacy Analysis

+-------------+-------------+-------------+-------------+-------------+
| **Treatment |             |             |             |             |
| Groups**    |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **Group A** | **Group B** | **Group C** | **Group**   | **Group**   |
|             |             |             |             |             |
| **rhGH**    | **rhGH +    | **GLN**     | **B vs C**  | **A vs C**  |
|             | GLN**       |             |             |             |
| **(n=16)**  |             | **(n=9)**   |             |             |
|             | **(n=16)**  |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **Change in |             |             |             |             |
| Total IPN   |             |             |             |             |
| Calories    |             |             |             |             |
| \[kcal/wk\] |             |             |             |             |
| /           |             |             |             |             |
| (p-value)** |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **-4338.3** | **-5751.2** | **-2633.3** | **-3117.9   | **-1705.0   |
|             |             |             | (\<0.001)** | (0.005)**   |
+-------------+-------------+-------------+-------------+-------------+
| **Change in |             |             |             |             |
| IPN or      |             |             |             |             |
| Lipid       |             |             |             |             |
| frequency   |             |             |             |             |
| \[d/wk\]    |             |             |             |             |
| (p-value)** |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| **-3.0**    | **-4.2**    | **-2.0**    | **-2.2      | **-1.0      |
|             |             |             | (\<0.001)** | (0.025)**   |
+-------------+-------------+-------------+-------------+-------------+

**Gastrointestinal Drugs Advisory Committee**

**Questions for NDA 21-597, Serostim for SBS**

**Continued**

3.  The primary endpoint was change in Total IPN volume. Only 1 of the 3
    components (IPN volume) was recorded between week 6 and 18. Is the
    measurement of IPN volume adequate to demonstrate durability of
    effect? If not, what do you recommend as a minimum follow up period?

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4.  The data were primarily derived from a single, nutritional support
    tertiary care center. Are these data generalizable to the population
    of short bowel syndrome patients?

5.  Are there specific safety concerns considering the potential for
    long term use of

> rh-GH in the treatment of short bowel syndrome patients?

6.  Do the data support the safety and effectiveness of rh-GH alone or
    in co-therapy

with glutamine in patients with short bowel syndrome? Are there any
additional studies that you would recommend, e.g., dose finding?