Acute Bacterial Sinusitis Historical Overview and Goals for Today

1. Acute Bacterial SinusitisHistorical Overview and Goals for Today Renata Albrecht, M.D. Division of Special Pathogen and Immunologic Drug Products ODEIV/CDER

2. In the beginning, • Amoxicillin • “infections of the ear, nose and throat …” • Augmentin 4:1 (1984) • “Sinusitis infections caused by beta-lactamase producing strains of H. influenzae and B. catarrhalis” • Other products • Upper respiratory tract infections … • Approval was based on clinical trials in which patients on both arms has sinus puncture for microbiological documentation of infection on entry

3. Acute Bacterial Sinusitis • Approval was (is) based on demonstration of • Efficacy (= clinical and microbiological data) • Safety • Other relevant data include • In vitro activity for target pathogens • Pharmacokinetic data • Tissue/sinus drug levels • Generally one of multiple indication • Including other respiratory indications such as community acquired bacterial pneumonia, acute bacterial exacerbation of chronic bronchitis, acute bacterial otitis media

4. Points to Consider 1992 • In response to concerns about challenge of performing sinus puncture for microbiological diagnosis, PTC document introduced 2 trial recommendation: • “Clinical only” trial – comparative trials with “rigid” clinical and radiographic criteria to select population expected to have bacterial sinusitis; microbiologic diagnosis not required • “Microbiologically-driven” clinical trial – [often non-comparative] where only patients on test drug have sinus puncture to document bacterial pathogen at entry

5. Advisory Committee - 1994 • Consider whether endoscopic sampling of sinus to obtain specimen for culture is acceptable alternative to sinus puncture and aspiration. • Presentations • FDA, Consultants, and Industry • Committee recommendations • Sinus puncture is gold standard – studies to compare endoscopy to puncture have not been done (Talbot presented preliminary data from one trial) and endoscopy is not precise, reproducible or standardized • Continue to evaluate role of endoscopy

6. Acute Bacterial Sinusitis Draft Guidance - 1998 • 2 clinical trials recommended - • 1. Clinical only, comparative trial, active control • Rigorous case definition based on signs and symptoms; radiographic findings • Duration >7 but <28 days (of URI) • Signs and symptoms (Facial pain, pressure, tightness, purulent discharge, congestion, cough, HA, fever, bad breath, altered smell perception, toothache, tearing, periorbital swelling…) • Radiographic – evidence of opacity, mucosal swelling, or air-fluid level • Evaluation at baseline, and outcome assessment at 1-2 weeks post therapy

7. Acute Bacterial SinusitisDraft Guidance – 1998 (cont.) • 2. Microbiologically-driven, open [often non-comparative] clinical trial, looking at clinical and microbiological outcome in each patient • Clinical and Radiographic criteria as for comparative trial • Microbiology – maxillary sinus puncture and aspiration at baseline • Gram’s stain for WBC and bacterial morphology • Isolation and quantification of pathogen (>104CFU/mL) • 25 Streptococcus pneumoniae, 25 Hemophilus influenzae, 15 Moraxella catarrhalis, 10-20 Staphylococcus aureus • Evaluation at baseline and outcome assessed 1-2 weeks post therapy [Microbiological outcome extrapolated from clinical outcome]

8. Today’s Meeting • We have experience with about 10 NDAs since 1990; is the advice in the draft Guidance to Industry (acute bacterial sinusitis) useful and sound? Is it time to revisit the guidance? • The clinical only trial may be more acceptable to patients, but have we lost diagnostic specificity? • In the microbiologically-driven study -- less patients are exposed to the sinus puncture -- what are the data we are seeing? • Are the two trial designs recommended in the guidance yielding reliable data on drug efficacy?

9. Acute Bacterial Sinusitis: Overview Jack M. Gwaltney, M.D. Professor of Internal Medicine Division Head Epidemiology and Virology University of Virginia Description of Sinus Puncture Austin Sydnor, M.D. University of Virginia • Statistical Considerations in Clinical • Trial Design in ABS • Thomas Fleming, Ph.D. • University of Washington

10. Clinical Evaluation of ABS: Diagnostic Considerations Carl N. Kraus, M.D. Medical Officer Division of Special Pathogen and Immunologic Drug Products Observations from Past Approvals for ABS Janice Pohlman, M.D. Medical Officer Division of Anti-Infective Drug Products Clinical Trial Design in ABS: Considerations for Future Guidance John Powers, M.D. Lead Medical Officer, ODE IV

11. Question 1 How does one ensure that patients in clinical trials of acute bacterial sinusitis have bacterial disease? Please discuss the methods of obtaining microbiologic data including sinus punctures and nasal endoscopy.

12. Question 2 • Please discuss the issues of trial design in the study of acute bacterial sinusitis. Please include in your discussion: • The strengths and limitations of placebo-controlled trials and non-inferiority trials. Please discuss how one determines a non-inferiority margin in non-inferiority trials for this indication. • The strengths and limitations of comparative microbiologic data

13. Question 3 Please discuss the issues of measuring outcomes in patients in trials of acute bacterial sinusitis. Please include in your discussion measuring time-to-resolution of symptoms as an endpoint compared to fixed endpoints.