# Presentation: 674030

## Exubera® Pfizer PharmaceuticalsNew Drug Application 21-868 Hypoglycemia in Type 1 Patients

**Endocrine and Metabolic Drugs AC Meeting**
**Silver Spring, Maryland**
**September 8, 2005**
**Joy Mele, MS**
**FDA Statistical Reviewer**
**Division of Biometrics 2**

**Center for Drug Evaluation and Research**** **

## Outline of Presentation

**Protocol 107 **
**Entry criteria**
**Collection of the data**
**Measures of hypoglycemic risk**
**Focusing on severe hypoglycemia in Study 107**
**The post-hoc “FDA” definition of hypoglycemia**
**Characteristics of the events**
**Conclusion regarding hypoglycemic risk for INH versus SC**

## The Protocol and Hypoglycemic Events

**Entry criteria**
**No more than 1 severe hypoglycemic event or any hospitalization due to poor glycemic control in previous 6 months or  during run-in **
**Two definitions**
**Hypoglycemic event**
**Severe hypoglycemic event**

## The Protocol and Hypoglycemic Events

**Case Report Form Data**
**Symptoms  Y/N**
**Glucose (several sources)**
***Was subject unable to self treat?***
***Did subject exhibit CNS symptoms?***
***Was blood glucose 49 mg/dL or lower OR***
***   ******Did symptoms reverse with CHO?***
**Severity: Mild, Moderate, Severe**

## Measures of Hypoglycemic Risk

**Percentage of patients with at least one event**
**Event rate as total number of events over total exposure (e.g. person-months)**
**“****complementary information”**** **
**[ADA Workgroup, Diabetes Care, May 2005]**
**BUT may not be enough information.**

## Study 107 Hypoglycemia% Pts w/ at least 1 event	   Events per pt-month

**RR      1.0              0.97             1.3                       0.89              0.7              2.5**

## Study 107 Distribution of Severe Events

**             ****# of pts by total number of events**
**	****	****	**_**0**__**	**__**1**__**	**__**2**__**	**__**3**__**	**__**4**__**	**__**5**__**	**__**12**_
**INH****	****       85    10****	****3****	****2****	****1****	****1****	**** 1**
**SC****	****       90     8****	****4****	****1****	****0****	****0****	**** 0**
**Medians of 0; Wilcoxon rank sum test p=0.30**
**Recurrent events analysis w/o pt w/12 events, decreases estimate from 2.25 to 1.65, NS **

## Study 107 Patients with 3+ events (INH 27/43, 63%) 

## Study 107 INH Patients with More than 3 Severe Hypoglycemic Episodes

**5036-7117:  35 yo M with 4 severe episodes (Wks 3, 10, 16, 24), no clear pattern**
**5102-7639:  54 yo F with 5 severe episodes; all within 1 week; no further severe episodes after insulin reduced and bedtime snack added**
**5007-7988:  19 yo F with 12 severe episodes; 9 episodes in 2 weeks while home over college winter break after 7 weeks on INH**

## Conclusion for Severe Hypoglycemia

**One patient with 12 severe events overly influences estimates of risk based on survival models of recurrent events.**
**No significant treatment difference between INH and SC in Study 107. Results are consistent with those seen in Study 106.**

## FDA-defined Events Glucose 36 OR unable to treat oneself

***What characteristics  differentiate these events from total events?***

## Study 107 FDA-defined Hypoglycemic Events

**91/103 INH patients with 971  events**
**94/103 SC  patients with 1327 events**
**	****	****	****	****	****	**_**INH**__**	**__**	**__**SC**_
**Glucose ********36 ****	****	****         923           1293**
**Unable to treat oneself        39               20**
**Both****	****	****	****	****           9                14**

## Glucose Distributions by Severity Total Hypoglycemic Events in Study 107

**FDA  Events Patient Means**
**INH   32.2    SC   31.5  **

## Study 107 Severity Scores

- FDA events Patient Means
-  INH  1.5    SC   1.5

## Study 107Symptomatic Hypoglycemic Events

- FDA events Patient Means
- INH   0.83     SC   0.78

## Study 107 Frequency of FDA-defined Events

## Study 107 Comparison of FDA-events

**91/103 INH patients with 971  events**
**94/103 SC  patients with 1327 events**** **
**Medians  INH 6 events     SC 8 events**
**Wilcoxon rank sum test p=0.09**

## Closing Comments

**Hypoglycemic events are similar in quantity and characteristics between the INH-treated patients and the SC-treated patients**
**Rates of hypoglycemia should not be summarized and analyzed based on total events without carefully examining the distribution of the events across patients. “Outliers” may grossly skew the estimates of risk.**