Scientific Advisory Committee on Respiratory and Allergy Therapies (SAC-RAT)

Date: 2006-12-10

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Discussion Paper:
Clinical Requirements for Second-Entry Inhaled Corticosteroids for use in the Treatment of Asthma

OVERARCHING PRINCIPLES:

At a minimum the following two trials are required:

1. An adequate, well-controlled therapeutic equivalence trial comparing the test and reference products.
2. A pharmacokinetic (PK) study to evaluate the systemic exposure to inhaled corticosteroid from the test product relative to the reference product as a surrogate for possible long-term systemic effects.

DISCUSSION ITEMS:

With Regard to the Therapeutic Equivalence Study:

1. Study Design to Investigate the Therapeutic Equivalence between Test and Reference Products

Either parallel or cross-over design would be considered acceptable as long as they meet the following criteria:

• Double blind
• Randomised
• Adequate sample size
• Adequate washout period for cross-over design to eliminate carry-over effect
• Sufficient duration (The duration of the therapeutic equivalence study should be appropriate for the drug to be investigated. We would consider a minimum of 12 weeks duration for parallel design. For cross-over design, justification should be submitted for the proposed duration.)
• Use of placebo to show assay sensitivity ( Adequate justification must be provided if placebo is not used.)
• Use of more than one dose for both test and reference products
• Inclusion of patients with mild, moderate and severe asthma (Justification should be provided if patients in a particular group of severity are not studied.)

2. Efficacy Endpoints for Therapeutic Equivalence Trial

FEV₁ is considered to be an acceptable primary endpoint.

In addition, the following may be considered as secondary endpoints:

• Airway hyper-responsiveness such as the provocation challenge (PC₂₀) causing a 20% fall in FEV₁ with methacholine and/or AMP
• Airway inflammation, such as sputum eosinophil counts and exhaled nitric oxide (NO)
• Asthma symptoms
• Asthma exacerbation
• The use of rescue medications

3. Clinical Significance Criteria

For FEV₁ as the primary endpoint to be measured,the difference between test and reference to placebo of 12% would be considered clinically significant.

4. Therapeutic Equivalence Criteria

The recommended criterion to demonstrate therapeutic equivalence is as follows:

The 95% confidence interval of the relative mean FEV₁ (on the log scale) of the test to the reference product should be within 80-125%.

With Regard to the Pharmacokinetic Study:

The PK study should be a single dose study in which the following PK parameters should be determined: AUC_t, AUC_i, C_max, T_max, t_1/2 and K_el.

The following standards will be applied to the pharmacokinetic study:

• The 90% confidence interval of the relative mean AUC_t of the test to reference product should be within 80-125%
• The relative mean measured C_max of the test to reference product should be between 80-125%