1. Design of Clinical Trials of Antibiotic Therapy for Acute Otitis Media
Colin D. Marchant, M.D.
Boston University School of Medicine
and
Tufts University School of Medicine
FDA Anti-Infective Drugs Advisory Committee Meeting, July 11, 2002

2. Correlation Between Clinical and Bacteriological Outcome in Acute Otitis Media
Clinical Failure
Clinical Success
Culture-negative
on day 3-7
2/66 (3%)
P < 0.001
17/253 (7%)
Culture-positive
on day 3-7
21/57 (37%)
15/40 (38%)
Carlin et al
J Pediatr
118:178-83, 1991
Dagan et al
Pediatr Infect Dis J 17:776-82, 1998

3. The Pollyanna Phenomenon Measuring the Efficacy of Anti-bacterial Drugs in Acute Otitis Media
Bacteriologic
Efficacy
Clinical Efficacy
in Bacterial AOM
Clinical
Efficacy
Drugs appear, and are equal
Excellent drugs appear
worse than they really are
Poor drugs look better
than they really are
Placebo
Marchant CD, et al J Pediatr 1992;120:72

4. Sample Sizes Required to Detect Differences Between Antibacterial Drugs for Acute Otitis Media (AOM): Comparison of Bacteriologic Versus Clinical Outcomes in a Trial of 2 Drugs With Varying Bacteriologic Efficacy (Half the patients would be in each arm of a study)
Measuring the comparative efficacy of antibacterial agents for acute otitis media: The “Pollyanna Phenomenon.” Colin D. Marchant, Susan A. Carlin, Candice E. Johnson, and Paul A. Shurin. J Pediatrics 1992;120:

5. Clinical Impact of Drug Efficacy
Based on Marchant et al J. Pediatr 1992;120:72

6. Clinical Impact of Drug Efficacy
Based on Marchant et al J. Pediatr 1992;120:72

7. Design Issues Otitis Media specific: Sample size Outcome measures
All are important, but in relative order of importance:
Otitis Media specific:
Sample size
Outcome measures
Patient selection – low/high risk
Diagnostic criteria at entry
General:
randomized, double-blind, compliance, etc.

8. Four Trial Designs “Double Tap”
“Tap at Entry and Tap of Clinical Failures”
“Tap at Entry with Clinical Outcome”
Clinical Criteria for Entry and Outcome

9. Parameters Used in Sample Size Calculations
Significance level = 0.05
Power = 0.90
Inverse sine method
All sample sizes are for a 2-limbed trial with half of subjects in each limb

10. Sample Sizes and # of Tympanocenteses (Taps) Various Study Designs Good Drug (90%) vs. Placebo (30%)
# Recruited
# Taps
# Analyzed
Double “Tap” 40 70 30
“Tap” & “Tap” of Failures 80 52
Initial “Tap” &
Clinical Outcome
195
146
542
Based on data of Marchant et al J. Pediatr 1992;120:72 and Dagan et al
Pediatr Infect Dis J 1998;17:776.

11. Sample Sizes and # of Tympanocenteses (Taps) Various Study Designs Good Drug (90%) vs. Poor Drug (50%)
# Recruited
# Taps
# Analyzed
Double Tap 83
145 62
Tap & Tap of Failures
280
304
210
Initial Tap &
Clinical
371
278
1136
Based on data of Marchant et al J. Pediatr 1992;120:72 and Dagan et al
Pediatr Infect Dis J 1998;17:776.

12. Sample Sizes and # of Tympanocenteses (Taps) Various Study Designs Good Drug (90%) vs. Fair Drug (70%)
# Recruited
# Taps
# Analyzed
Double Tap
262
458
196
Tap & Tap of Failures
928
966
696
Initial Tap &
Clinical
1176
882
4146
Based on data of Marchant et al J. Pediatr 1992;120:72 and Dagan et al
Pediatr Infect Dis J 1998;17:776.

13. Sample Size for Measuring Efficacy of Antibiotics in Acute Otitis Media
Depends on the outcome selected
Depends on population studied
Minimum standard: Large enough to demonstrate that a new antibiotic is better than no antibiotic – otherwise efficacy has not been measured
Adequate standard: Should exclude a 20% difference in bacteriologic efficacy between antibiotics – ensure that no more than 40,000 children per million children treated will remain symptomatic because of unmeasured inferiority

14. Recommended Guidance for Industry Sample Size
Response rates (eradication, clinical, etc) should be based on data from clinical trials, not assumption or expert opinion
Trial size must be large enough to demonstrate that a drug is a least better than a placebo.
The difference between two drugs should be a clinically important one, such as persistent symptoms at a rate of 40,000 per million prescriptions, i.e. a 20% difference in bacteriologic efficacy
Should also consider the power of sub-group analyses, e.g. organism specific response rates

15. Outcomes for Measuring the Efficacy of Antibiotic Therapy in Acute Otitis Media
Directly meaningful, or validated against meaningful outcomes
Objective or at least reproducible
Sensitive (are affected by antibiotic therapy)
Timely – measured at a time point when antibiotic therapy has an effect
Supported by evidence (not assumption)

16. Outcomes in Clinical Trials of Antibiotic Therapy in Acute Otitis Media
1. “Double Tap”
2. “Tap and Tap of
Clinical Failures”
3. “Tap at entry and
Clinical Outcome”
4. Clinical Outcome
Information increases
Eradication by MIC
Pathogen eradication rates,
Correlations with PK/PD,
etc.
Sample Size
Decreases

17. Recommended Guidance for Industry Trial Design - Tympanocentesis
“Double tap” studies are preferred - have been validated, provide more information, and require the smallest sample size, and the fewest number of taps (among studies with taps)
“Tap and Tap of Clinical Failures” is an alternative that if large enough will provide useful information
If clinical outcomes other than symptomatic response are to be used as outcomes, they should be validated

18. Recommended Guidance for Industry Population Selection/Enrichment
Trials should include “enriched’ populations: The young, treatment failure, prior antibiotic therapy, day care, etc are the most challenging cases and clinicians need to know whether antibiotics are efficacious in these patients. These patients should be included, not excluded from clinical trials

19. Recommended Guidance for Industry Diagnostic Criteria
Symptoms: should have at least one of: earache, irritability, fever
Otoscopic exam: should have at least one opaque, bulging eardrum with reduced mobility
A trial site should isolate pathogens from at least 70% of cases at entry

20. Ethical Issues
Is it ethical to license, market and prescribe drugs without knowing that they are efficacious (pass the tap water standard)?
Is it ethical to perform drug trials in humans that will not yield scientifically valid data?
Is it ethical to perform tympanocentesis?
Is it ethical to perform double tympanocentesis studies?

21. Do the benefits outweigh the risks?
Tympanocentesis is briefly painful but not permanently harmful
The benefits of the knowledge gained outweigh the risks
Still, there is a need for research into the effectiveness of various methods of systemic and topical analgesia/anesthesia for tympanocentesis should be performed (industry should sponsor such studies).