# Presentation: 177390

## 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

_**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**_**  **

_**Choice of Outcome**_

_**Timing of Outcome**_

## Timing of Clinical Outcomes in Trials of Antibiotic Therapy for Acute Otitis Media 

**Antibiotic Therapy   ****               Post Antibiotic Therapy**

**48-72 Hrs**

**Day 4-6**

**“****End of Therapy”**
**   ****Day 10-12**

**   ****Day 28-30**
**“****Test of Cure”**

## Effect of Antibiotic Treatment on Earache in Severe AOM

**   ****1    2    3    4    5**

**Mean**
**Pain**
**Score**

**1.0**

**Placebo**

**Penicillin**

**Mygind et al**
**Clin  Otolaryngol**
**1981;6:5**

**Day**

*****

*****

******* p < 0.01**

## Treatment of Severe AOM

_**% initial treatment failure**_

** **

**Placebo &**
**Myringotomy **

**Amoxicillin &**
**Myringotomy**

**         ****N=34****	****	****	****  N=96****	****         N=156****	****	**
**         ****23.5% **                11.5%                9.6% ****

****  P< 0.01                            Kaleida, et al. *****Pediatrics, 1991***

**Amoxicillin**

## 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 

**from Leibowitz et al ICCAC Abstract #1968, Sept 2000**

**Relapses vs New Infections determined  for *****Streptococcus pneumoniae*****  by**
**PFGE and serotyping, and for *****Haemophilus influenzae***** by beta-lactamase**
**production**

**N=39**

**N=34**

**N=21**

**N=9**

## 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**_

**P = 0.001**

**Carlin et al. Pediatr 1991; 118:178**

- N=253

- N=40

## Early eradication of pathogens from middle ear fluid during antibiotic treatment of acute otitis media is associated with improved clinical outcome

**Early eradication of pathogens from middle ear fluid during antibiotic treatment of acute otitis media is associated with improved clinical outcome**

**Bacteriologic Failures**
**Culture (+) n = 57**

**Dagan et al, PIDJ 17; 776-82, 1998. **

**N = 123**** **

**Bacteriologic Success**
**Culture (-) n = 66**

**Clinical status**
** ****from day 4-6**
**to day 10**

**Note: 91% of the clinical failures were culture (+) on day 4-5**

## Clinical Success Rates in Acute Otitis Media

*** *****P*****=0.001, ** *****P*****=0.013**

**Marchant CD et. al. J Pediatr 1992;120:72**

**Bacteriologic Success    236/253   (93.2%)**
**Bacteriologic Failure       25/40       (62.5%)**
**Non-Bacterial AOM         124/155    (80.0%)**

## The Pollyanna PhenomenonMeasuring the Efficacy of Anti-bacterial Drugs in Acute Otitis Media

**Marchant CD, et al J Pediatr 1992;120:72**

**Bacteriologic**
**    ****Efficacy**

**Clinical**
**Efficacy**

**Poor drugs look better**
**than they really are**

**Excellent drugs appears **
**worse than they really are**

**Placebo**

## The Pollyanna PhenomenonMeasuring the Efficacy of Anti-bacterial Drugs in Acute Otitis Media

**Marchant CD, et al J Pediatr 1992;120:72**

**Bacteriologic**
**Efficacy**

**Clinical**
**Efficacy**

**Poor drugs look better**
**than they really are**

**Excellent drugs appear **
**worse than they really are**

**Placebo**

**Clinical Efficacy**
**in  Bacterial AOM**

**Drugs appear, and are equal**

## 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**

## Slide 16

## 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 

**Bacteriologic Outcomes from Marchant et al *****J  Pediatrics***** 1992;120: 72-77**
**Clinical Outcomes based on Kaleida et al Pediatrics 1991;87:466 **

****  compared with**
**     ****myringotomy**
**     ****not placebo**

## Bacteriologic, Symptomatic and “Test of Cure” ** Outcomes in Trials of Antibacterial Therapy in Acute Otitis Media

**Recurrence rate**
**5%    10%     15%     20%     25%     30%**

**Bacteriologic Outcome**

**Symptomatic Outcome During Therapy**

**** “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**

**Drugs appear worse than they really are**

**Drugs appear better than they really are**

**Placebo**

## 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**

**Day 4-6**

**“****End of Therapy”**
**   ****Day 10-12**

**Dagan et al**

**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**

## 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**

**      ****Excellent drugs**
**appear worse than**
**they really are**

**      ****Poor drugs**
**look better than**
**they really are**

**Placebo**

**Based on Dagan et al. Pediatr Infect Dis J 1998;17:776.**

**        ****Drugs appear,**
**  ****and are equal**

**Test of Cure**
**Clinical**
**Outcome**

## 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.**
** **