1. Development of Antibiotics for Otitis Media: Past, Present, and Future Janice Soreth, M.D. Director Division of Anti-Infective Drug Products

2. Outline of the Past and Present 1977 Guidance 1992 Points-to-Consider Document 1992 IDSA/FDA Guidelines 1998 FDA Draft Guidance

3. Back to the Future?  tympanocentesis for all? single v. multiple?  clinical-only studies?  placebo-controlled trials?  trial versus trials Bottom line: What do we need, to know the drug works and is safe for children with otitis media?

4. Otitis Media: Incidence & Epidemiology 25,000,000 visits for otitis media yearly in the U.S. accounts for 1 out of 3 pediatric office visits by 1 year of age: 62% > 1 episode AOM; 17 % > 3 by 3 years of age: 80% > 1 episode AOM; 46 % > 3 categories: occasional AOM to otitis prone

5. 1977 FDA Guidance on AOM 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

6. 1977 FDA Guidance on AOM (continued) “In the absence of culture of middle ear fluid, no specific claim can be made regarding the effectiveness of any anti-infective drug.”

7. AOM in the 80s: What Happened no new formal guidance on otitis from FDA “internal discussions” on AOM centered on requirement to perform tympanocentesis on every child enrolled in a trial –procedure is difficult to do –too few are trained to do it –it’s hampering enrollment in trials –it costs too much Is there a better way to design AOM trials, and know whether a drug works or not?

8. 1992 Points-to-Consider Document on AOM 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

9. 1992 Points-to-Consider Document on AOM (continued) 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.

10. 1992 IDSA/FDA Guidelines on AOM 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

11. 1997 & 1998 FDA Draft Guidance on AOM 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

12. 1998 AOM Draft Guidance: Advisory Committee Recommendations With regard to the microbiologic endpoint: 1998: “Tympanocentesis obtained at the on-therapy visit should not be considered evidence of documented eradication. Rather, a negative culture result may represent antimicrobial suppression.” 2001: “Tympanocentesis obtained on therapy should be the primary microbiologic endpoint.”

13. 1998 AOM Draft Guidance: Advisory Committee Recommendations 1998 (continued) Enroll more patients < 2 years of age. Gain much more experience with penicillin- resistant organisms.

14. 1998 AOM Draft Guidance: Advisory Committee Recommendations 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

15. 2001 AC Recommendations Timing of assessment of clinical outcome: primary endpoint should be end of therapy visit ; late follow-up visit is an important secondary endpoint Would encourage follow-up as secondary with taps for failures

16. 2001 AC Recommendations (continued) Most informative tap: Consensus was taps on therapy and at the time of failure were needed Cure rates should be bacteria specific such that the cure rate exceeds the spontaneous cure rate by some arbitrary amount, say 10 or 20%

17. 2001 AC Recommendations (continued) Clinical only and Micro studies: Why would we want to do clinical only studies anymore for this indication? No meaningful efficacy data With high spontaneous cure rate, what information will be gained from them? Don’t see how can do efficacy studies without knowing the organism Therefore, tighten up inclusion criteria for clinical only study

18. Clinical case definition for AOM Experience tells us, AOM can be a difficult call Even when the inclusion criteria are tight, and case report forms document presence of specific objective criteria, there is a broad range of culture-positive results for investigators, from “low to high”

19. Back to the Future  clinical case definition: How strict is strict?  trial design considerations: tympanocentesis for one and all? baseline/on-therapy/at time of failure  endpoints and timing of assessments:  clinical-only studies  micro-based studies  non-inferiority v. superiority designs  placebo-controlled trials  spectrum of disease:  severity, chronicity  distinct patient populations

20. Back to the Future Question of the day: What do we need to know, what constitutes substantial evidence, that a novel antimicrobial drug works and is safe for children with otitis media?