1. Acute Bacterial Otitis Media Summary and Charge to the Committee Renata Albrecht, M.D. Division of Special Pathogen and Immunologic Drug Products ODEIV, CDER

2. Acute Bacterial Otitis Media Bacterial pathogens responsible for morbidity (some self limited disease) Drugs evaluated to treat bacterial pathogens Product Labeling includes bacterial pathogens (Viral OM - self limited illness)

3. Acute Bacterial Otitis Media DIAGNOSIS (AT BASELINE ) –Clinical signs and symptoms “Strict case definition” –Tympanocentesis Identify causative bacterial pathogen –Both !

4. Acute Bacterial Otitis Media ENDPOINTS & TIMING (RELATIVE TO BASELINE) Clinical –on therapy (time to resolution? Dr. Dagan ) –end of therapy ( 2 -7 day after last dose ?) Microbiological –on therapy extrapolate from clinical (no repeat tympano) tympanocentesis (day 3-5) –end of therapy (extrapolate from clinical?) BOTH !

5. Acute Bacterial Otitis Media POPULATIONS AOM –(e.g. pens, cephs, macrolides) Recurrent AOM Treatment failure (persistent, nonresponsive) AOM –(e.g fluoroquinolones, high dose betalactams) –Do these enable enrichment for PRSP?

6. Clinical Trial Designs CONTROLLED CLINICAL TRIALS –Active controlled –Placebo controlled

7. Clinical Trial Design, Diagnosis, & Endpoints ACTIVE Control (noninferiority)* –All patients have a clinical evaluation at baseline & endpoint only - no tympanocentesis = “clinical only” and baseline tympanocentesis = “single tap” add baseline & on therapy tympanocentesis = “double tap” *vs. Superiority (would also reduce sample size)

8. Clinical Trial Design, Diagnosis, & Endpoints PLACEBO Control (superiority) –All patients would have a clinical evaluation at baseline & endpoint only - no tympanocentesis = “clinical only” and baseline tympanocentesis = “single tap” add baseline & on therapy tympanocentesis = “double tap” 3-arm

9. Constraints: Rules & Regulations 21 CFR 314.126 Adequate and well-controlled studies! –placebo, dose ranging, no treatment, active, or historical control In patients with the disease! –“The method of selection of subjects provides adequate assurance that they have the disease or condition being studied... “ –(compare/contrast to patients with “clinical syndrome”)

10. Drug development in otitis media Practical issues –What are barriers to performing tympanocentesis in clinical trials? –Are placebo-controlled trials practical in the U.S. at this point in time? –How acceptable are these procedures to patients and parents? –Can we perform trials more efficiently while still obtaining useful data?

11. Questions 1.Should a comparative trial incorporating tympanocentesis be required for demonstrating the effectiveness of drugs for AOM? In your response, address the following:  The role of each of the types of studies discussed: clinical-only studies, single tympanocentesis trials, double tympanocentesis trials, placebo-controlled trials  The utility of a strict case definition versus use of tympanocentesis at baseline for diagnosis of AOM  The relative value of comparative versus non- comparative data in trials that include tympanocentesis.

12. Question 1 1a) Is tympanocentesis the best way to establish the diagnosis of acute bacterial otitis media? 1b) Is a controlled study incorporating tympanocentesis the best study design to establish that an antimicrobial agent (antibacterial) is safe and effective in treating acute bacterial otitis media?

13. Question 1 1c) Is it reasonable to consider placebo- controlled studies in evaluating drugs for AOM? –If yes, can this be considered in all patients with AOM, or should this be restricted to a subset (and which subset)? –Role of tympanocentesis?

14. Questions 2.Does the committee agree with the definitions of recurrent AOM and AOM treatment failure, used to identify a separate population of patients for study? In your response, address the following:  The use of these definitions to identify patients more likely to have penicillin-resistant Streptococcus pneumoniae  The likelihood of differences in treatment response in this population vs. general AOM  (is this a means to suggest that agents developed for this separate population should not be used in all AOM)

15. Questions Question 2 Definitions Recurrent Acute Otitis Media  3 episodes of AOM over the last 6 months  4 episodes of AOM over the past year Treatment Failure During Therapy: No improvement observed in signs and symptoms of AOM after at least 48 hours of antimicrobial management, or Post Therapy: Presentation with signs and symptoms of AOM within 7 days of completing a course of therapy for acute otitis media

16. Question 2 Is the subpopulation of patients defined as having recurrent OM/treatment failure OM reasonable for drugs intended for drug- resistant pathogens (conversely, not intended an initial therapy in AOM)?

17. 3. Do double tympanocentesis trials have a role in demonstrating effectiveness of drugs a) for general AOM? b) for recurrent/treatment failure AOM? In your response, address the following:  The timing of clinical and microbiologic assessments  The relative importance of clinical vs. microbiological assessment, including the value of an on-therapy tympanocentesis in a child who is clinically improving  The ability of the on-therapy tympanocentesis results to predict clinical outcome  Sufficient study sites (including sites within the U.S.) to perform double tympanocentesis Questions

18. Question 3 When should clinical studies with double tympanocentesis (baseline and on- treatment) be requested? –In all AOM studies –in studies of recurrent OM/ nonresponsive OM

19. Other Issues for Discussion  Alternative methods of clinical outcome assessment (e.g., time to resolution of AOM symptoms/signs)  Activity against the major pathogens in AOM is expected: How should existing data (e.g., PK/PD, in vitro susceptibilities) that suggest decreased activity of a drug for an AOM pathogen be taken into account in the clinical trial design?  Age distribution of patients within placebo-controlled and active-controlled studies  Other factors (e.g., day care attendance, prior antibiotics as exclusion criteria, seasonality)

22. Issues raised Diagnosis (of acute bacterial otitis media) Tympanocentesis (establish presence of pathogen) –baseline –on therapy Clinical trials design –active control –placebo control –(no control) Endpoints