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, November 7, 2001

2. Outcomes in Trials of Antibacterial Drugs for AOM
Choice of Outcome
Clinical: Symptomatic improvement, or symptomatic & otoscopic improvement, etc.
Bacteriologic: eradication of bacteria
Bacteriologic/Clinical: Clinical improvement plus eradication of bacteria in clinical failures
During Therapy
End of Therapy
After Therapy
Timing of Outcome

3. Timing of Clinical Outcomes in Trials of Antibiotic Therapy for Acute Otitis Media
Antibiotic Therapy Post Antibiotic Therapy
“End of Therapy”
Day 10-12
Day 28-30
“Test of Cure”
Day 4-6
48-72 Hrs

4. Effect of Antibiotic Treatment on Earache in Severe AOM
Placebo
1.0
Penicillin
Mean
Pain
Score
* p < 0.01 * *
Mygind et al
Clin Otolaryngol
1981;6:5
Day

5. Treatment of Severe AOM
% initial treatment failure
Placebo &
Myringotomy
Amoxicillin &
Myringotomy
Amoxicillin
N= N= N=156
23.5% ** % % **
** P< Kaleida, et al. Pediatrics, 1991

6. Amoxicillin vs Placebo for Non-severe AOM
Kaleida et. al. Pediatrics 1991;87:466

7. Bacteriology of Clinical Recurrences of AOM 1 Month After Completion of Treatment
Relapses vs New Infections determined for Streptococcus pneumoniae by
PFGE and serotyping, and for Haemophilus influenzae by beta-lactamase
production
from Leibowitz et al ICCAC Abstract #1968, Sept 2000

8. Clinical Recurrences of Acute Otitis Media After Therapy
Not reduced by prior antibiotic therapy (Kaleida et al, etc)
Common in patients with eradication of the initial pathogen (Leibowitz, Carlin, DelBaccaro)
New infections more common than relapses (Leibowitz, Carlin, DelBaccaro)

9. Correlation of Bacteriologic and Clinical Outcomes in Acute Otitis Media after 3-6 days of Antibiotic Therapy
Bacteria Eradicated
from the Middle Ear
Bacteria Persist
in the Middle Ear
N=253
N=40
P = 0.001
Carlin et al. Pediatr 1991; 118:178

10. Early eradication of pathogens from middle ear fluid during antibiotic treatment of acute otitis media is associated with improved clinical outcome
N = 123
Cure
36 (63%)
Failure
21 (37%)
Cure
64 (97%)
Failure
2 (3%)
Clinical status
from day 4-6
to day 10
Culture result
on day 4-5
Bacteriologic Failures
Culture (+) n = 57
Bacteriologic Success
Culture (-) n = 66
Note: 91% of the clinical failures were culture (+) on day 4-5
Dagan et al, PIDJ 17; , 1998.

11. Clinical Success Rates in Acute Otitis Media
Bacteriologic Success /253 (93.2%)
Bacteriologic Failure / (62.5%)
Non-Bacterial AOM / (80.0%)
* P=0.001, ** P=0.013
Marchant CD et. al. J Pediatr 1992;120:72

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

13. 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

14. 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:

15. 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

17. Sample Sizes Required to Detect Differences Between an Antibacterial Drug with 90% Bacteriologic Efficacy and Drugs with Fair Efficacy (70%), Poor Efficacy (50%), or Tap water (30%) in Clinical Trials of Acute Otitis Media
Marchant et al J Pediatrics 1992;120: 72-77

18. Sample Size Calculations for Clinical Outcomes
* White = Actual Data Yellow = Extrapolated Data

19. Sample Sizes Required to Detect Differences Between an Antibacterial Drug with 90% Bacteriologic Efficacy and Drugs with No Efficacy (30%) Poor Efficacy (50%), Poor Efficacy (70%), or in Clinical Trials of Acute Otitis Media
** compared with
myringotomy
not placebo
Bacteriologic Outcomes from Marchant et al J Pediatrics 1992;120: 72-77
Clinical Outcomes based on Kaleida et al Pediatrics 1991;87:466

20. Bacteriologic, Symptomatic and “Test of Cure”
Bacteriologic, Symptomatic and “Test of Cure” ** Outcomes in Trials of Antibacterial Therapy in Acute Otitis Media
Bacteriologic Outcome
Symptomatic Outcome During Therapy
Recurrence rate
5% 10% % % % %
Drugs appear worse than they really are
Drugs appear better than they really are
Placebo
** “Test of Cure” = symptomatic failures during therapy + clinical recurrences after therapy
Based on data from: Marchant CD et al 1992;120:72 & Kaleida et al Pediatrics 1991;87:466

21. Sample Sizes Required to Detect Differences Between an Antibacterial Drug with 90% Bacteriologic Efficacy and Drugs with Fair Efficacy (70%), Poor Efficacy (50%), or Tap water (30%) in Clinical Trials of Acute Otitis Media
Bacteriologic and Symptomatic Outcomes from Marchant et al J Pediatrics 1992;120: 72-77
Test of cure assumes no effect of antibiotics on recurrence rates as demonstrated by Kaleida et al Pediatrics 1991;87:466

22. Timing of Outcomes in Trials Correlating Clinical and Bacterriologic Endpoints in Acute Otitis Media
Antibiotic Therapy Post Antibiotic Therapy
Dagan et al
Day 4-6
“End of Therapy”
Day 10-12
Carlin/
Marchant
et al
Carlin et al J Pediatr 1991;118:178
Marchant et al J Pediatr 1992;120:72
Dagan et al Pediatr Infect Dis J 1998;17:776

23. Outcome if Clinical Failure Day 4-10
Bacterial AOM: Bacteriologic, Bacteriologic/Clinical and Clinical Outcomes (“Double Tap”, “Tap and Tap of Clinical Failures”, and “Single Tap” with Clinical End of Therapy and Test of Cure Outcomes)
Bacteriologic
Efficacy
Bacteriologic
Outcome if Clinical Failure Day 4-10
End of Therapy
Clinical
Outcome
Test of Cure
Clinical
Outcome
Drugs appear,
and are equal
Poor drugs
look better than
they really are
Excellent drugs
appear worse than
they really are
Placebo
Based on Dagan et al. Pediatr Infect Dis J 1998;17:776.

24. Sample Sizes Required to Detect Differences Between an Antibacterial Drug with 90% Bacteriologic Efficacy and Drugs with No Efficacy (30%) Poor Efficacy (50%), Fair Efficacy (70%), in Clinical Trials of Bacterial AOM (Tympanocentesis Trials)
Based on Dagan et al Pediatr Infect Dis 1998;17:776

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

26. Clinical Trial Sizes to Distinguish Between Drugs with 90% and 30% Bacteriologic Efficacy The Tap Water Standard
Study Designs: Initial Bacteriologic Diagnosis:
* Assumes bacteria are isolated from 75% of AOM cases

27. Clinical Trial Sizes to Distinguish Between Drugs with 90% and 30% Bacteriologic Efficacy The Tap Water Standard
Trial Designs - No Tympanocentesis:

28. Clinical Trial Sizes to Distinguish Between Drugs with 90% and 50% Bacteriologic Efficacy The Poor Drug Standard
Study Designs: Initial Bacteriologic Diagnosis:
* Assumes bacteria are isolated from 75% of AOM cases

29. Clinical Trial Sizes to Distinguish Between Drugs with 90% and 50% Bacteriologic Efficacy The Poor Drug Standard
Trial Designs - No Tympanocentesis:

30. Clinical Trial Sizes to Distinguish Between Drugs with 90% and 70% Bacteriologic Efficacy The Fair Drug Standard
Study Designs: Initial Bacteriologic Diagnosis:
* Assumes bacteria are isolated from 75% of AOM cases

31. Clinical Trial Sizes to Distinguish Between Drugs with 90% and 70% Bacteriologic Efficacy The Fair Drug Standard
Trial Designs - No Tympanocentesis:

32. Conclusions
1. Most trials using bacteriologic diagnosis and clinical outcome have been too small to distinguish between a good drug and tap water and all have been too small to distinguish between a good drug and a fair drug

33. Conclusions
2. Most trials using clinical diagnosis and a clinical outcome have been too small to distinguish between a good drug and tap water

34. Conclusions
3. Data do not support the use of the “Test of Cure” outcome as a scientifically valid outcome in clinical trials of antibacterial drugs for AOM

35. Recommendations
1. Clinical trial data in support of licensure of antibiotics for AOM should, at a minimum, exceed the tap water standard.

36. Recommendations
2. The FDA should convene a panel of experts to examine the design of antibiotic trials for AOM using scientific data and principles, and revise the current “Guidance for Industry”
accordingly.

37. Recommendations
3. If double tympanocentesis studies are to be conducted, research into the effectiveness of various methods of systemic and topical analgesia/ anesthesia for tympanocentesis should be performed (industry should consider sponsorship of such studies).

38. Recommendations
4. Improved methods for trials with clinical outcomes (e.g. more sensitive outcomes, enriched populations, etc.) should be investigated in rigorous studies. However, large numbers of subjects may still be required to demonstrate efficacy in clinical studies despite such refinements.