1. Acute Otitis Media: Lessons Learned Thomas Smith, M.D. Division of Anti-Infective Drug Products

2. 2 1998 Draft Guidance: Study Considerations Statistically adequate and well-controlled multicenter trial Rigid case definitions with specific subjective and objective diagnostic and effectiveness parameters clearly defined Baseline tympanocentesis need not be performed; tap of failures strongly encouraged to document inadequately treated pathogens

3. 3 1998 Draft Guidance: Study Considerations Tympanocentesis trial Silent on comparative vs. noncomparative Establish acceptable outcome in at least: –25 patients with H. influenzae –25 patients with S. pneumoniae –15 patients with M. catarrhalis Tap of failures strongly encouraged

4. NDA 50-710: Azithromycin4 Example: Clinical-only Trial Double-blind, double-dummy, randomized trial 350 patients enrolled from 9 U.S. sites Ages 6 months-12 years –60% >2 years; mean age 2.7 years

5. NDA 50-710: Azithromycin5 Clinical-only Trial: MITT Outcomes Study DrugComparator 95% CI EOT Success 139/160 142/161 (%) (87) (87) -9.2, 6.5 TOC Cure 114/151 116/154 (%) (75) (75)-10.2, 10.5 EOT=Day 12-16; TOC=Day 28-32

6. NDA 50-710: Azithromycin6 Example: Tympanocentesis Trial Open-label, noncomparative trial with baseline tympanocentesis 248 patients enrolled from 22 U.S. and Latin American sites Ages 6 months-12 years –65% >2 years; mean age 3.4 years 127 (51%) with positive cultures

7. NDA 50-710: Azithromycin7 Tympanocentesis Trial: Outcomes by Pathogen EOT Success (%) 95% CI Overall 213/240 (89) 84.5, 93.0 Pathogen S. pneumoniae 70/76 (92) 85.4, 98.8 H. influenzae 30/42 (71) 56.3, 86.3 M. catarrhalis 10/10 (100) 95.0, 100 EOT=Day 8-12

8. 8 Comments from Advisory Committee, November 2001 Limitations of clinical-only trials Issues with microbiologic data Age distribution of patients Need for revision of draft guidance

9. Nelson JD, McCracken GH9 Pediatric Infectious Disease Journal Newsletter, February 2002 “The supporting studies for these two regimens have shortcomings, similar to studies of other therapeutic agents in acute otitis media. It is time for the FDA to establish strict criteria for conducting clinical trials in patients with AOM if a new antibiotic is to be approved for therapy.

10. Nelson JD, McCracken GH10 Pediatric Infectious Disease Journal Newsletter, February 2002 “Such clinical trials should include a predominance of children younger than 2 years, a tympanocentesis at diagnosis to establish etiology, a repeat tympanocentesis at 4-5 days in a subset of patients to establish bacteriologic cure or a repeat ear tap in patients who are considered clinical failures, and follow-up evaluation at 10-14 days as the primary clinical endpoint.”

11. 11 Issues for Discussion Value of comparative studies with diagnostic tympanocentesis Role of clinical-only studies

12. 12 1998 Draft Guidance: Study Considerations Pathogens listed in label “Acceptable eradication rates” If product fails to have acceptable clinical and microbiologic effectiveness against all 3 major pathogens, it should be listed only for those it has eradicated; restricted listing as not a product for first line therapy Restriction is based on empiric nature of treatment and need for first-line therapies to be effective against all common pathogens

13. NDA 50-622: Cefixime13 Example: Pathogen Labeling Indications –Otitis media caused by H. influenzae, M. catarrhalis, S. pyogenes* (* fewer than 10 infections) Clinical Studies –Response rate of S. pneumoniae to cefixime approximately 10% lower and that of H. influenzae or M. catarrhalis approximately 7% higher than rates of these organisms to active control drugs

14. NDA 50-586: Ceftibuten14 Example: Pathogen Labeling Indications –Acute bacterial otitis media due to H. influenzae, M. catarrhalis, or S. pyogenes –NOTE: Although ceftibuten used empirically was equivalent to comparators in the treatment of clinically and/or microbiologically documented acute otitis media, the efficacy against S. pneumoniae was 23% less than control. Therefore, ceftibuten should be given empirically only when adequate antimicrobial coverage against S. pneumoniae has been previously administered. Clinical Studies

15. 15 Issues for Discussion Demonstration of efficacy against all major pathogens Inclusion of pathogens in label

16. 16 1998 Draft Guidance: Inclusion Criteria Clinical-only trials ordinarily should not enroll children less than 6 months old No recommendations about age distribution in studies Problem: unrepresentative study populations Examples

17. 17 1998 Draft Guidance: Exclusion Criteria Tympanostomy tubes Otitis externa Systemic anti-infective therapy –Clinical-only: 7 days prior to enrollment –Clinical/micro: 3 days prior to enrollment Antimicrobial prophylaxis for recurrent OM

18. 18 Issues for Discussion Inclusion criteria: age distribution of children enrolled in trials, other methods of capturing population of greatest interest Exclusion criteria: for clinical/micro studies, permit enrollment of recently- treated patients, patients receiving prophylaxis

19. 19 1998 Draft Guidance: Evaluation and Outcome Evaluations –Entry –On-therapy (3-5 days): strongly recommended –End-of-treatment: optional –Test-of-cure (2-4 weeks after entry) –Late post-treatment: optional Outcome –Primary endpoint is test-of-cure visit

20. 20 Advisory Committee, January 2001 Relevant clinical test of cure is at end of therapy; later follow-up is important secondary endpoint To assess microbiologic response, most informative repeat taps are on therapy, followed by at time of clinical failure

21. 21 Summary: Issues for Discussion Value of comparative studies with diagnostic tympanocentesis Role of clinical-only studies Demonstration of efficacy against all major pathogens Inclusion of pathogens in label

22. 22 Summary: Issues for Discussion Inclusion criteria: age distribution of children enrolled in trials, other methods of capturing population of greatest interest Exclusion criteria: for clinical/micro studies, permit enrollment of recently- treated patients, patients receiving prophylaxis