1. NDAC December 14, 2007 1 Clinical Endpoints for Nasal Decongestants Xu Wang, M.D., Ph.D. Medical Officer Division of Pulmonary and Allergy Products Nonprescription Drugs Advisory Committee Meeting December 14, 2007

2. NDAC December 14, 2007 2 Overview Nasal congestion and its pharmacologic treatment Types of clinical studies for nasal decongestants Assessment of nasal congestion in clinical studies

3. NDAC December 14, 2007 3 Introduction Nasal congestion –A subjective complaint –Reported by patients as stuffy nose, stopped up nose, nasal stuffiness, and clogged up nose –Management of nasal congestion may include environmental control, physical measures, surgical procedures, and pharmacologic treatment

4. NDAC December 14, 2007 4 Introduction OTC monograph oral nasal decongestants –Pseudoephedrine and phenylephrine OTC monograph indication for nasal decongestants –Temporary relief of nasal congestion due to common cold, hay fever or other upper respiratory allergies (allergic rhinitis)

5. NDAC December 14, 2007 5 Types of Clinical Studies in Common Cold Naturally occurring cold –Volunteers are enrolled when they develop a naturally occurring cold –Study may comprise patients with a number of different cold viruses –Enrollment completed over longer period of time Induced cold –Volunteers inoculated with a specified dose of a single known cold virus –May be conducted with a shorter period of enrollment

6. NDAC December 14, 2007 6 Types of Clinical Studies in Allergic Rhinitis Outpatient natural exposure (real life) studies –Over 2 weeks for seasonal allergic rhinitis –Over 4 weeks for perennial allergic rhinitis “Day in the Park” studies –Single day exposure in an outdoor setting –Affected by weather, relevant allergens, and season Environmental Exposure Unit (EEU) studies –Controlled allergen exposure in an indoor setting –A sensitive pharmacodynamic model

7. NDAC December 14, 2007 7 Clinical Endpoints for Nasal Decongestants Nasal congestion scores Nasal airway resistance (NAR) and other objective measures –Nasal minimal cross-section area (MCA) –Nasal cavity volume (VCA)

8. NDAC December 14, 2007 8 Patient Self-Assessed Nasal Congestion Scores Nasal congestion scores directly address the symptom of nasal congestion The nasal congestion symptom is the OTC Monograph indication of nasal decongestants Nasal congestion scores are usually rated on an ordinal scale Two types of nasal congestion scores –Reflective scores measure the symptom severity over a predefined time period, assessing efficacy over the entire dosing interval –Instantaneous scores measure the symptom severity at a time preceding the time of dosing to assess the efficacy at the end of dosing interval

9. NDAC December 14, 2007 9 Nasal Airway Resistance A function of nasal airflow and an objective measure of nasal patency Provides useful information as a supportive efficacy endpoint for nasal decongestants Does not directly assess patient symptoms, does not directly address the Monograph indication of nasal decongestants May be discordant with patient self-assessed severity of nasal congestion

10. NDAC December 14, 2007 10 Study Design Considerations Double-blind, placebo-controlled, parallel group study design –Placebo control and double blind are critical because of the subjective nature of the primary efficacy endpoint –Active control is recommended

11. NDAC December 14, 2007 11 Summary Patient self-assessed nasal congestion scores are DPAP’s preferred primary efficacy endpoints in clinical studies of nasal decongestants. A drug for nasal congestion indication should be tested in naturally occurring cold studies, or in outpatient natural exposure allergic rhinitis studies. These clinical studies of nasal decongestants should be double-blind, placebo-controlled, parallel-group studies. Nasal airway resistance can be used as a secondary or supportive efficacy endpoint in clinical studies of nasal decongestants.

12. NDAC December 14, 2007 12 Division of Pulmonary and Allergy Products 10903 New Hampshire Ave, BLD 22 Silver Spring, MD 20993-0002 Phone: 301-796-2300 Fax: 301-796-9728