# Presentation: 593078

## FDA Advisory Committee for Pharmaceutical Science and Clinical PharmacologyOffice of Generic DrugsFood and Drug Administration

- Paul M Dorinsky, M.D.
- VP, Global Respiratory Clinical Research
- TEVA Pharmaceuticals

- TEVA Global Respiratory R&D

- July 23, 2008

## ICS-Containing Inhaled Products in the US (MAT 5/08)

- Approximately **31 Million Prescriptions/Year**
- Approximately **$7 Billion Annually**
- Therefore, there is a need for achievable guidelines to be developed to allow generic products to reach the US market

- TEVA Global Respiratory R&D

- July 23, 2008

## Presentation Outline

- Background
- Overview of Dose-Response Data for Inhaled Corticosteroids (ICS) in Asthma
- Implications of shallow ICS dose response for evaluating ICS bioequivalence
- Alternative proposal for demonstrating ICS bioequivalence

- TEVA Global Respiratory R&D

- July 23, 2008

## Background

**Background**

- Scientific rationale for Dose-Response as a method for establishing ICS Dose Equivalence
- Internal Study Validity – Assay Sensitivity
- Establishment of Dose Relationship Between Test and Reference ICS

**Test ICS Dose A**

**Test ICS Dose B**

**Reference ICS Dose A**

**Reference ICS Dose B**

- TEVA Global Respiratory R&D

- July 23, 2008

## Overview of Dose-Response Data for Inhaled Corticosteroids (ICS) in Asthma

- Phase IIb dose response studies have generally been conducted by investigating different doses in distinct populations rather than evaluating the full range of doses in the same patient population
- In general, even the lowest dose of an ICS has significant activity that is close to the maximum effect of the drug
**MICE Study** [ACRN study by Szefler et al; JACI 2002 ]
- ICS Evaluated
- BDP CFC (n=15) at doses of 168, 672 and 1344 mcg per day
- Fluticasone propionate CFC (n=15) at doses of 88, 352, and 704 mcg per day
- Near maximal FEV1 and PC20 effects occurred at low to medium doses for both ICS
-  The high dose did not significantly increase efficacy for either ICS
- Dose response extremely shallow

- TEVA Global Respiratory R&D

- July 23, 2008

## Dose Response Studies Where ICS Dose Response was Minimal

| Reference | Primary Endpoint | Design | ICS Doses | Key Outcome | Comment |
| --- | --- | --- | --- | --- | --- |
| Taylor et al
[AJRCCM 1999] | AMP Challenge |  9-10 patients/arm
 14 day x-over | Ciclesonide 100, 400 and 1600 mcg BD |  Dose response established, but actual differences in AMP were small |  No DR for Sputum Eo’s or Lung Function |
| Jones et al
[ERJ 2002] | eNO |  12-14 patients/arm
 8 week study
 Parallel Group | BDP HFA 50 , 100, 200 and 500 mcg/day
 |  Difference between highest and lowest doses, but eNO difference was small |  No differences between adjacent doses |
| Pearlman et al
[JACI 2005] | FEV1 |  249-257 patients/arm
 12 week study
 Parallel Group | Ciclesonide 80, 160 and 320 mcg QD |  All treatments significantly improved FEV1
 |  No Dose Response
 |
| Inman et al
[AJRCCM 2001] | Allergen Challenge  |  6 patients/arm
 6 day x-over
 | Mometasone 50, 100 and 400mcg BD |  All treatments improved the Late Phase Response |  Minimal Dose Response |
| Fish et al
[JACI 2000] | Oral Steroid Sparing |  43-46 patients/arm
 12 week study
 Parallel Group | Mometasone 400 and 800 mcg BD
 |  Both treatments Reduced Oral Steroid Use |  No Dose Response |

- TEVA Global Respiratory R&D

- July 23, 2008

## Dose Response Studies Where ICS Dose Response was Observed

| Reference | Primary Endpoint | Design | ICS Doses | Key Outcome | Comment |
| --- | --- | --- | --- | --- | --- |
| Busse et al
[JACI 1999] | FEV1 %Predicted |  Severe Asthma (FEV1 51-53%)
 50-59 patients/arm
 6 week study
 Parallel Group | BDP CFC 100, 400 and 800 mcg/day
BDP HFA 100, 400 and 800 mcg/day |  Dose Potency Ratio Established
 Significant Dose Response for 100mg Vs 800mcg dose only |  FEV1 differences between adjacent doses was very small |
| Pauwels et al
[NEJM 1997] | Exacerbations |  210-215 patients/arm
 1 year study
 Parallel Group | BUD 100 and 400mcg BD
BUD 100 and 400mcg BD + Formoterol 12mcg BD |  Dose Response for Exacerbation Rate |  No Dose Response for FEV1, Sx or SABA use |
| Bateman et al
[AJRCCM 2004] | Asthma Control |  548-585 patients/arm
 1 year study
 Parallel Group
 Complex Design | Fluticasone/Salmeterol 100/50, 250/50 and 500/50mcg BID
Fluticasone 100, 250 and 500mcg BID |  All Treatments Improved Asthma Control
 |  Dose Response Observed but  was Small |

- TEVA Global Respiratory R&D

- July 23, 2008

## Interim Summary

- Although some studies did discriminate between ICS dose levels, no design has been shown to be reproducibly useful in demonstrating an ICS dose response
- Regardless of the design or endpoint utilized, clinically relevant and statistically significant differences between ICS doses is generally minimal

- TEVA Global Respiratory R&D

- July 23, 2008

## Implications of shallow ICS dose response for evaluating ICS bioequivalence: Finney Assay

**With a shallow dose response curve, the CI will be wider as compared with a dose response curve that is steep **

**Log Dose of ICS**

**% Change in FEV****1**

**% Change in FEV****1**

- TEVA Global Respiratory R&D

- July 23, 2008

## Simulation Relating Total Sample Size and Slope of Log Dose Response When Limits for 95% Confidence Interval of Relative Potency is 0.8 to 1.25

-  **What type of dose response can be expected for an ICS?**
- . Based on the MICE study [Szefler et al;  JACI 2002] using methacholine response
-  Slope for BDP **0.18**
-  Slope for FP **0.07**

**N ~ 175**

**N ~ 500**

- TEVA Global Respiratory R&D

- July 23, 2008

## Alternative proposal for demonstrating ICS bioequivalence: Key Principles

- Following In Vitro Characterization demonstrating bioequivalence of the Test and Reference ICS, The clinical Program will:
-  Ensure Internal Study Validity – Assay Sensitivity
-  Ensure the Relationship Between Test and Reference ICS is characterized
-  Ensure Adequate Assessment of Safety and Efficacy in Relevant Populations

- TEVA Global Respiratory R&D

- July 23, 2008

## Key Elements of the Clinical Program

- For the development of generic [505(j)] inhaled corticosteroid products, TEVA proposes:
- Clinical Pharmacology study
- Randomized, two-way, crossover study in healthy volunteers or patients for each dose
- Equivalence for AUC0-t,  and Cmax, ( 90% confidence interval between limits of 0.80 to 1.25)
- Clinical Efficacy Study – Adults and Adolescents
- Randomized, parallel group, 12-week  study in asthma patients (one study per strength)
- Placebo or active comparator for assay sensitivity
- Pre-Dose FEV1 or other established efficacy measure as primary endpoint
- Non-inferiority of the test product and the reference product and superiority to placebo
- Safety assessed via adverse events and other safety measures as appropriate (e.g., clinical labs, ECGs, etc)
- Clinical Safety Study - Pediatrics
- Extrapolation of efficacy from adults to children
- Safety study (and or PK study) evaluating the test and reference product to show comparable safety (and or systemic exposure) of the two products.

- TEVA Global Respiratory R&D

- July 23, 2008