Clinical Study Options for locally acting nasal suspension products

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

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

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

4. Types of Studies: • “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 CDER / FDA

5. Types of Studies: • 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 CDER / FDA

6. Types of Studies: • 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,… CDER / FDA

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

8. Dose ln Dose Model of Nasal Spray Dosage Form Performance Clinical/PD Measurements Dosage Form Performance (Device and Formulation) Membrane (Nasal) Site of Activity Therapeutic Effect Drug in Solution Dosage Form GI Tract, Lung Blood Toxic/Ther. Effect Pharmacokinetic Measurement CDER / FDA

9. What is the Question for the Clinical study in the BE setting? • Is clinical study confirmatory or pivotal? • Depends on findings and interpretation of In Vitro and BE comparisons • “Confirmatory” • Study necessary to confirm a lack of important clinical differences as a part of larger BE package • “Pivotal” • Clinical study to primarily establish BE CDER / FDA

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

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

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

13. FDA experience (continued): • 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 • Other endpoints in standard trials (e.g., HRQOL instruments) • unproven as superior in sensitivity to dose-response CDER / FDA

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

15. If “Equivalence” In Vitro and Systemic Exposure are shown: • 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 • Under this paradigm • ? Best Study - 2 wk. Clinical, EEU, Park??? CDER / FDA