# Presentation: 178680

## Clinical Trials of Acute Otitis Media

- John Alexander, M.D., M.P.H.
- Anti-Infective Drugs Advisory Committee
- November 7, 2001

## 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.”

## 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- Draft Guidance for Industry Documents (1998)

## 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*

## 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.”

## 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

## 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

## 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)

## 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

## AC Meetings on AOM

- Fall 1997: Ceftriaxone for AOM
- Discussion focused on product
- Comments on resistant *S. pneumoniae*
- Comments related to study design

## 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

## 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

## AC Meetings on AOM

- Nov. 2001 - Zithromax for AOM
- Discussion focused on product
- Clinical trial design

## Issues for Discussion

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

## 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).