CLINICAL EFFICACY TESTING for NASAL DRUGS

Mary M. Fanning, M.D., Ph.D.

Associate Director for Medical Affairs

Office of Generic Drugs, FDA

June 4, 1999

Nasal Drug Products

Prescription: corticosteroids antihistamines anticholinergics

OTC: mast cell stabilizercromolyn sodium

BA/BE for Nasal Drug Products

BA • Release of drug substance from drug product to the site of action

• cannot be measured by conventional pharmacokinetics

BE - comparison of a test product to a precursor product

• to-be-marketed product to a pivotal clinical trial material

• generic drug product to a reference listed drug

Clinical Endpoints

• Highly variable

• Relatively insensitive to detect differences between products

• Unequivocally establish effectiveness

Suspensions:

Solutions:

• Bioequivalence studies with clinical endpoints are necessary

• systemic exposure studies

• in vitro studies

• In vitro studies

Indication to be studied:

Seasonal Allergic Rhinitis

Document bioequivalence for all labeled indications

Treatment Study Design not prophylaxis

Sensitivity Evaluation

• Dose-response relationship

• Second dose may differ by 2- to 4- fold

• Increase sensitivity

–lower dose may be below the recommended labeled dose (1/4 or 1/2)

Study Endpoints

Before and during treatment

• Patient self-rated total nasal symptoms score (TNSS)

• Composite score

runny nose, sneezingnasal itching, congestion

Study Endpoints (con’t)

• Onset of action

• Efficacy at the end of the dosing interval

Inclusion/Exclusion Criteria

• History of Seasonal Allergic Rhinitis

• Positive Allergy test for specific allergens

• Exclude patients with other diseases

• Patients with defined minimum level of symptom severity

Study Designs

• Traditional Treatment Study

• Day(s) in the Park Study

• Environment Exposure Unit Study

Traditional Treatment Study

• Two weeks of conventional therapy

• Randomized, double-blind, placebo- controlled, parallel group

Traditional Treatment Study (con’t)

• Symptom measurement twice a day reflective scores

• End of dosing interval symptom measurement - instantaneous scores

• Adverse Event (ADE) monitoring, Lab

Traditional Treatment Study (con’t)

• Relatively insensitive

• Large sample size

• Frequently used design

Day(s) in The Park Study

• Randomized, double-blind, placebo- controlled, parallel group

• Park exposure for pre-specified period, one to two days

• Dosing prior to or at beginning of study

• Safety ADE

Day(s) in The Park Study (con’t)

• Maximize exposure to allergens

• Shorter duration

• Less experience with study design

• Sample size? pilot study

Environmental Exposure Unit Study

• Randomized, double-blind, placebo- controlled, parallel group design

• Controlled indoor environment with controlled allergen release

• Pre-treatment exposure to relevant allergens

Environmental Exposure Unit Study (con’t)

• Screen for symptomatic responders

• Duration - full dosing interval

• Safety ADE

• Control allergen exposure

Environmental Exposure Unit Study (con’t)

• Select responders to specific allergens

• Limited experience with this model

• Availability of units

• Sample size? pilot study