1. Acute Otitis Media Trials: Evolution of Guidance Janice Soreth, M.D. Division of Anti-Infective Drug Products January 30, 2001

2. Guidelines for Clinical Evaluation of Anti-Infective Drugs on AOM (1977) number of trials: not addressed case definition: clinical evidence of AOM (“evidence of inflammation of tympanic membrane and middle ear”) tympanocentesis: required in both studies at baseline. Second tap desirable to obtain data on MEF concentrations and promptness of bacteriologic cure. endpoints: both clinical and microbiologic test of cure: not addressed; 4 weeks of follow-up

3. Guidelines for Clinical Evaluation of Anti-Infective Drugs on AOM (1977) “In the absence of culture of middle ear fluid, no specific claim can be made regarding the effectiveness of any anti-infective drug.”

4. Points-to-Consider Document on AOM (1992) number of trials: two suggested - “clinical only” study (no tympanocentesis at baseline) to establish equivalence to an approved product - one clinical/microbiologic study with tympanocentesis at baseline case definition: should be rigid tympanocentesis: strongly encouraged in those patients judged to be therapeutic failures endpoints: clinical; clinical and microbiologic test of cure: not specifically addressed

5. Points-to-Consider Document on AOM (1992) The open micro study should establish acceptable microbial and clinical outcome in at least 25 patients with H. influenzae, in at least 25 patients with S. pneumoniae, and in at least 15 patients with M. catarrhalis.

6. IDSA/FDA Guidelines on AOM (1992) number of trials: two suggested - a micro study (100 patients) - a comparative clinical trial (tap optional); double-blind case definition: clinical criteria listed tympanocentesis : tap required in those patients who are not clinical successes (failure, relapse, recurrence) endpoints : clinical; clinical and microbiologic test-of-cure: 1-2 weeks after completion of therapy

7. AOM Evaluability Criteria Advisory Committee Recommendations (1997 & 1998) number of trials: two suggested - a micro study, non-comparative; increase numbers - a comparative clinical trial case definition: tighten, tighten, tighten tympanocentesis : repeat tap at study day 3-5 as critical measure of treatment efficacy; perform tympanocentesis in all failures endpoints : primary efficacy endpoints are clinical cure at TOC and pathogen eradication. test-of-cure: TOC visit 2-4 weeks after study entry. Enhance efforts to enroll patients with penicillin- resistant organisms

8. AOM Evaluability Criteria Advisory Committee Recommendations (1998) With regard to the microbiologic endpoint: “Tympanocentesis obtained at the on-therapy visit should not be considered evidence of documented eradication. Rather, a negative culture result may represent antimicrobial suppression.”

9. AOM Evaluability Criteria Advisory Committee Recommendations (1998) Enroll more patients < 2 years of age. Gain much more experience with penicillin- resistant organisms.

10. “All Comers” v. “Enriched” Trial Increase the number of patients under 24 months of age Enroll patients with ruptured TM’s, history of recurrent otitis, antibiotic prophylaxis Include patients with recent AOM who have failed a course of antibiotics