Acute Otitis Media Trials: Evolution of Guidance

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 Documenton 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 Documenton 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 lt 2 years of age.
• Gain much more experience with penicillin-resistan
  t organisms.

10
All Comers v. Enriched Trial

• Increase the number of patients under 24 months
  of age
• Enroll patients with ruptured TMs, history of
  recurrent otitis, antibiotic prophylaxis
• Include patients with recent AOM who have failed
  a course of antibiotics