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

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

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

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 1 2 3 4 5 Day

Treatment of Severe AOM % initial treatment failure Placebo & Myringotomy Amoxicillin & Myringotomy Amoxicillin N=34 N=96 N=156 23.5% ** 11.5% 9.6% ** ** P< 0.01 Kaleida, et al. Pediatrics, 1991

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

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

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)

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

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; 776-82, 1998.

Clinical Success Rates in Acute Otitis Media Bacteriologic Success 236/253 (93.2%) Bacteriologic Failure 25/40 (62.5%) Non-Bacterial AOM 124/155 (80.0%) * P=0.001, ** P=0.013 Marchant CD et. al. J Pediatr 1992;120:72

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

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

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: 72-77.

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

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

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

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

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% 15% 20% 25% 30% 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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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.

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).

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.