1. Clinical Trials of Acute Otitis Media John Alexander, M.D., M.P.H. Anti-Infective Drugs Advisory Committee November 7, 2001

2. 2 History Kefauver-Harris Amendments (1962) Clinical Evaluation of Anti-Infective Drugs (1977) –“It is necessary to confirm the presence of exudate in the middle ear by pneumotoscopy and needle aspiration to obtain fluid for culture.” –“In the absence of culture of middle ear fluid, no specific claim can be made regarding the effectiveness of any anti-infective drug.”

3. 3 History Points to Consider Document (1992) –“Statistically adequate and well-controlled multi-center trial … establishing equivalence or superiority to an approved product” –“Open study … using tympanocentesis … at baseline to establish microbiologic etiology” –At least 25 patients with S. pneumoniae –At least 25 patients with H. influenzae –At least 15 patients with M. catarrhalis FDA/IDSA (CID Supplement Nov. 1992) Draft Guidance for Industry Documents (1998)

4. 4 Draft AOM Guidance Two Studies recommended: –“A statistically adequate and well-controlled multi- center trial … establishing safety and effectiveness” –“Another trial … using tympanocentesis … at baseline to establish microbiologic etiology” –At least 25 patients with S. pneumoniae –At least 25 patients with H. influenzae –At least 15 patients with M. catarrhalis

5. 5 Draft AOM Guidance For the first trial (clinical-only study): –Ordinarily should not enroll children <6 months –Rigid case definitions –Baseline tympanocentesis need not be performed –“Tympanocentesis of patients judged to be therapeutic failures is strongly encouraged to document potential specific bacterial pathogens not adequately treated in the trial.”

6. 6 Draft AOM Guidance For the second trial (Micro Study): –“Post-therapy tympanocentesis is encouraged [in] patients judged to be therapeutic failures” –  2 investigators in geographically diverse regions –Acceptable clinical and microbiologic effectiveness against all three microorganisms –Resistance and S. pneumoniae, 25 patients may be insufficient

7. 7 Draft AOM Guidance Study Visits –Entry Visit –On Therapy (3-5 days): Strongly recommended –End-of-Treatment: Optional –Test-of-Cure: 2-4 weeks after entry –Late Post-Treatment Follow-Up: Optional

8. 8 AC Meetings on AOM Guidance for Industry (March 1997) Ceftriaxone for AOM (Nov. 1997) Guidance Revisions (July 1998) Augmentin ES-600 for AOM (Jan. 2001)

9. 9 AC Meetings on AOM Spring 1997 - Presentation of Guidance –Baseline clinical findings –Timing of the TOC visit –Number of S. pneumoniae isolates in light of increasing resistance –Follow-up of middle ear effusion out to 30 days

10. 10 AC Meetings on AOM Fall 1997: Ceftriaxone for AOM –Discussion focused on product –Comments on resistant S. pneumoniae –Comments related to study design

11. 11 AC Meetings on AOM 1998 - Guidance revisited –Presentation of changes based on Spring ‘97 AC –Letter from CDC to FDA: “Since clinical-only studies would need to be prohibitively large to detect a difference if one truly existed between two drugs … smaller bacteriologically-driven study would be more effective” –Industry response during the AC meeting

12. 12 AC Meetings on AOM Jan. 2001 - Augmentin ES-600 for AOM –Discussion focused on product –Timing for the test-of-cure visit –Assessment of bacteriology in clinical failures

13. 13 AC Meetings on AOM Nov. 2001 - Zithromax for AOM –Discussion focused on product –Clinical trial design

14. 14 Issues for Discussion Should clinical-only trials continue or should all enrolled patients have a tympanocentesis at baseline? Should non-comparative microbiology studies continue?

15. 15 Issues for Discussion Should guidance incorporate stratification by age (< 2 years)? If so, what proportion of patients should be under the age of 2 years? –In your discussion, please comment on the merits of studies with clinical information only, studies with tympanocentesis, ideal timing of clinical assessments (end-of-therapy v. later follow-up), and alternative study designs (comparative trials with microbiology, double-tap studies, placebo-controlled studies with early escape).