1. CDER / FDA1 Clinical Study Options for locally acting nasal suspension products Robert J. Meyer, MD Director, Div. Of Pulmonary and Allergy Drug Products CDER / FDA

2. 2 Introduction n What are the options for a ‘clinical’ study? n What is the question to be answered? n Given the question, what is the best answer? n Observations and recommendations

3. CDER / FDA3 What are the options? n The disease in question is Allergic Rhinitis, primarily experienced and assessed subjectively n The basis of approval has been clinical studies with subjective symptom scoring – TNSS (rhinorrhea, congestion, sneezing, itch) n PD questions (onset of action, appropriate dose/interval) frequently addressed with differing designs

4. CDER / FDA4 Types of Studies: n “Natural” Clinical Study – Generally 2 - 6 week Parallel group study looking at comparative changes in TNSS over the treatment period – Patients are enrolled prior to or at start of season, randomized when symptomatic – Also allows for assessment of safety and tolerability over a reasonable period of use

5. CDER / FDA5 Types of Studies: n EEU study – Takes patient out of season and exposes them to high levels of a specific pollen to which they are all allergic – Symptoms are assessed in the short-term (over a period of hours) – Often used for assessing onset of effect, dose- finding

6. CDER / FDA6 Types of Studies: n Day in the Park Study – Cohort of patients with known allergen sensitivity, but low level of symptoms – Taken to an outdoor setting (“Park”) in cohort for natural exposure to allergen – Short-term efficacy and safety assessed – Also used for assessing onset, assessing dose- effects, duration of effects,…

7. CDER / FDA7 Types of Studies: n DPADP regards the natural clinical study to be the most informative for approval purposes n DPADP regards EEU and Day in the Park studies as more pharmacodynamic n Other “objective” endpoints in any of the study designs (nasal patency, markers of inflammation) are regarded as interesting, but not clinically validated

8. CDER / FDA8 What is the Question for the Clinical study in the BE setting? n Is clinical study confirmatory or pivotal? – Depends on findings and interpretation of In Vitro and BE comparisons n Confirmatory – Study to confirm lack of important clinical differences n Pivotal – Study to establish BE based on clinical outcomes

9. CDER / FDA9 If Intent is to Confirm Other Data: n Design to broadly assure no important clinical differences n Rigorous showing of dose-response and strict equivalence between T and R not required n Comparison may be on one dose level of each to show comparable efficacy, safety and tolerability

10. CDER / FDA10 If Intent is to Establish BE: n Design must show sensitivity of the ‘assay’ (i.e., can detect dose-response); AND n Results must show that the dose-response curve of the T + R are “equivalent” n Clinical study would also compare relative safety and tolerability

11. CDER / FDA11 FDA experience: n Standard clinical studies of locally acting nasal products can easily fulfill confirmatory role n BE role would be VERY difficult with standard design / endpoints n PD studies (EEU, Day-in-the-Park studies) – MAY be better approach to BE, but unknown – May have a role in confirmatory setting

12. CDER / FDA12 FDA experience (continued): n Objective local PD endpoints (e.g., using markers of inflammation or measures of nasal patency) – unproven in sensitivity to dose-response – and/or not clinically validated n Other endpoints in standard trials (e.g., HRQOL instruments) – unproven as superior in sensitivity to dose- response

13. CDER / FDA13 If “Equivalence” In Vitro and Systemic Exposure are shown: n Main uncertainty will be drug particle size in the suspension formulation – More problematic in aqueous spray than aerosol n FDA now contemplating shifting the question asked of the clinical study in the BE package n Clinical Study would NOT “trump” lack of equivalence from In Vitro or systemic BA

14. CDER / FDA14 If “Equivalence” In Vitro and Systemic Exposure are shown: n Confirmatory Study: – Examine lowest dose of T+R – Statistical comparison between the lowest dose of T and R (vs. Placebo) – Assure that T is not meaningfully different from R n Under this paradigm – ? Best Study - 2 wk. Clinical, EEU, Park???